Nothing Special   »   [go: up one dir, main page]

US4994461A - 1,4-dihydropyridine enantiomers - Google Patents

1,4-dihydropyridine enantiomers Download PDF

Info

Publication number
US4994461A
US4994461A US07/401,453 US40145389A US4994461A US 4994461 A US4994461 A US 4994461A US 40145389 A US40145389 A US 40145389A US 4994461 A US4994461 A US 4994461A
Authority
US
United States
Prior art keywords
denotes
methyl
aryl
alkyl
nitrophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/401,453
Inventor
Wolf-Rudiger Ulrich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Assigned to BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH reassignment BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ULRICH, WOLF-RUDIGER
Application granted granted Critical
Publication of US4994461A publication Critical patent/US4994461A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to novel enantiomers processes for their preparation, their use and medicaments which contain them.
  • the compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments.
  • 1,4-dihydropyridine derivatives substituted in the 4-position have pharmacologically useful properties. It is also known that these 1,4-dihydropyridine derivatives, provided that they are differently (asymmetrically) substituted in positions 2 and 6 and/or in positions 3 and 5 - have a centre of chirality in position 4. It is also known that the pharmacological properties of the 1,4-dihydropyridines can be influenced by the absolute configuration in the 4-position.
  • the invention thus relates firstly to pure dihydropyridine enantiomers of the formula I ##STR2## wherein Cy represents a cyclic radical of the formula ##STR3## in which Y denotes oxygen (O), sulphur (S), vinylene (--CH ⁇ CH--), azomethine (--CH ⁇ N--) or a group of the formula ##STR4## R1 and R2 are identical or different and denote hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,
  • R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl or 2-5C-acyl or together denote methylenedioxy, or denote amino or mono- or di-1-4C-alkylamino,
  • E denotes straight-chain or branched 2-5C-alkylene which may be substituted by 1-4C-alkoxy or aryl,
  • A denotes --CH 2 --C(R6)R7--CH 2 -- or --CH 2 --NR8--CH 2 --,
  • R6 denotes hydrogen (H) or aryl
  • R7 denotes aryl or arylcarbonyl
  • R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, aryl representing a ring of the formula ##STR5## wherein R9 and R10 are identical or different and have the meaning of hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl or trifluoromethyl, and heteroaryl represents a 5-membered or 6-membered heterocylic radical having one heteroatom or two identical or different heteroatoms from the group consisting
  • 1-6C-Alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl or, in particular, ethyl or methyl radical.
  • 3-7C-Alkoxyalkyl represents, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or, in particular, methoxyethyl radical.
  • halogen denotes bromine, fluorine and, in particular, chlorine.
  • 1-4C-Alkyl is straight-chain or branched and means, for example, a butyl, isobutyl, sec-butyl, tert-butyl propyl, isopropyl, ethyl or, in particular methyl radical.
  • 1-4C-Alkoxy contains, in addition to the oxygen atom, one of the above-mentioned 1-4C-alkyl radicals.
  • the methoxy radical and the ethoxy radical are preferred.
  • 1-4C-Alkoxy which is completely or partially substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, in particular, difluoromethoxy.
  • 1-4C-Alkoxycarbonyl contains in addition to the carbonyl group, one of the above-mentioned 1-4C-alkoxy radicals.
  • the methoxycarbonyl radical and the ethoxycarbonyl radical are preferred.
  • 2-5C-Acyl contains in addition to the carbonyl group, one of the above-mentioned 1-4C-alkyl radicals.
  • the acetyl radical is preferred.
  • Mono- or di-1-4C-alkylamino contains in addition to the nitrogen atom, one or two of the above-mentioned 1-4C-alkyl radicals.
  • Di-1-4C-alkylamino is preferred, in particular dimethyl-, diethyl- or diisopropylamino.
  • Straight-chain or branched 2-5C-alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and in particular ethylene or propylene.
  • Aryl represents phenyl which is substituted by R9 and R10.
  • the following radicals may be mentioned as examples of preferred aryl radicals: phenyl, 4-methoxyphenyl 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 3,6-dichlorophenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,4-methylenedioxyphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
  • Aryl-1-4C-alkyl represents one 1-4C-alkyl which is substituted by aryl.
  • the following radicals may be mentioned as examples of preferred aryl-1-4C-alkyl radicals: 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 1-phenylethyl, 2-phenylethyl, 3-chlorobenzyl, 2.5-dimethylbenzyl, 4-fluorobenzyl, 3-methylbenzyl and in particular benzyl.
  • Aryl-2-4C-alkenyl and aryl-2-4C-alkynyl represent alkenyl and alkynyl radicals having 2 to 4 carbon atoms, which are substituted by aryl.
  • the 3-phenyl-2-propenyl radical and the 3-phenyl-2-propynyl radical may be mentioned as examples.
  • Arylcarbonyl represents a carbonyl group which is substituted by aryl.
  • the 4-chlorophenylcarbonyl, 2-hydroxyphenylcarbonyl (salicyloyl), the 4-hydroxyphenylcarbonyl and in particular the 4-fluorophenylcarbonyl and the benzoyl group may be mentioned as examples of preferred arylcarbonyl groups.
  • radicals may be mentioned as examples of preferred (substituted) heteroaryl radicals: furyl, in particular 2-furyl, thienyl, in particular 2-thienyl, pyrimidyl, in particular 2-pyrimidyl, 3-cyano-2-pyridyl, thiazolyl, in particular 2-thiazolyl, and pyridyl, in particular 3-pyridyl and preferably 2-pyridyl.
  • Heteroarylcarbonyl represents a carbonyl group which is substituted by heteroaryl.
  • the nicotinoyl radical and the 2-furoyl radical may be mentioned as examples of preferred heteroarylcarbonyl radicals.
  • Heteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl.
  • Heteroaryl-1-4C-alkyl is, for example, 2-(2-pyridyl)-ethyl.
  • Diaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two aryl radicals.
  • Diaryl-1-4C-alkyl is, in particular diphenylmethyl (benzhydryl) or substituted benzhydryl, such as, for example, 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl, 4,4'-dimethoxyhydryl or 4,4'-dichlorobenzhydryl.
  • Heteroaryl-aryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl and aryl.
  • Diheteroaryl-aryl-1-4C-alkyl is, for example, 2-pyridylphenylmethyl.
  • Diheteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two heteroaryl radicals.
  • Diheteroaryl-1-4C-alkyl is, for example, dipyrid-2-ylmethyl.
  • Arylsulphonyl represents a sulphonyl group which is substituted by aryl.
  • the 4-chlorophenylsulphonyl radical and the 4-methoxyphenylsulphonyl radical may be mentioned as examples of preferred arylsulphonyl radicals.
  • the 2-phenylpropionyl radical may be mentioned as an example of an aryl-1-4C-alkylcarbonyl radical.
  • the cinnamoyl radical may be mentioned as an example of an aryl-2-4C-alkenylcarbonyl radical.
  • Suitable salts are all salts with acids.
  • the pharmacologically acceptable salts of the inorganic or organic acids usually used in the pharmaceutical industry may be mentioned in particular.
  • Pharmacologically unacceptable salts which may initially be obtained as products of the process, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the skilled worker.
  • suitable solvents of this type are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, metembonate, stearate, tosylate 2-hydroxy-3-naphtoate, 3-hydroxy-2-naphthoate or mesylate, as well as salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrynic acid, tienilic acid or 4-chlorosulphamoylbenzoic acid.
  • hydrochloride hydrobromide, hydriodide
  • the invention thus relates firstly to a novel pure 1,4-dihydropyridine enantiomer of the formula I which can be isolated or has been isolated for the first time.
  • the invention preferably relates to pure enantiomeric compounds of the formula I,
  • Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl
  • R1 and R2 are identical or different and denote 1-4C-alkyl
  • R3 denotes 1-4C-alkyl
  • E denotes ethylene or propylene.
  • A denotes --CH 2 --C(R6)R7--CH 2 -- or --CH 2 --NR8--CH--,
  • R6 denotes hydrogen (H) or phenyl
  • R7 denotes phenyl
  • R8 denotes aryl or benzhydryl, aryl representing a ring of the formula ##STR6## wherein R9 and R10 are identical or different and denote hydrogen (H), 1-4C-alkoxy or halogen,
  • An embodiment (embodiment a) of the invention comprises pure enantiomeric compounds of the formula 1, wherein Cy, R1, R2, R3, R4, R5 and E have the meanings stated at the outset,
  • A denotes --CH 2 --C(R6)R7--CH--
  • R6 denotes hydrogen (H)
  • R7 denotes aryl or arylcarbonyl aryl having the meaning stated at the outset, and the salts of these compounds.
  • the embodiment a can be characterised by the following formula Ia ##STR7## wherein the substituents and symbols have the meanings stated for embodiment a.
  • Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
  • R1 denotes methyl or ethyl
  • R2 denotes methyl or ethyl
  • R3 denotes methyl or ethyl
  • E denotes ethylene or propylene
  • R6 denotes hydrogen
  • R7 denotes phenyl, benzoyl, 4-chlorobenzoyl or 4-fluorobenzoyl, and their salts.
  • Particularly preferred compounds of embodiment a are those of the formula Ia, wherein
  • R1 denotes methyl
  • R2 denotes methyl
  • R3 denotes methyl
  • E denotes ethylene or propylene
  • R6 denotes hydrogen
  • R7 denotes phenyl, and their salts.
  • a further embodiment (embodiment b) of the invention comprises pure enantiomeric compounds of the formula I, wherein Cy, R1, R2, R3, R4, R5 and E have the meanings stated at the outset,
  • A denotes --CH 2 --NR8--CH 2 --
  • R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, aryl and heteroaryl having the meanings stated at the outset,
  • Embodiment b can be characterised by the following formula Ib ##STR8## wherein the substituents and the symbols have the meanings stated for embodiment b.
  • Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
  • R1 denotes methyl or ethyl
  • R2 denotes methyl or ethyl
  • R3 denotes methyl or ethyl
  • E denotes ethylene or propylene
  • R8 denotes phenyl, 2-methoxyphenyl. 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-pyridyl or benzhydryl, and their salts.
  • Particularly preferred compounds of embodiment b are those of the formula Ib, wherein
  • R1 denotes methyl
  • R2 denotes methyl
  • R3 denotes methyl
  • E denotes ethylene or propylene
  • R8 denotes phenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl or benzhydryl,
  • a further embodiment (embodiment c) of the invention comprises pure enantiomeric compounds of the formula I, wherein
  • R1 R2, R3, R4, R5 and E have the meanings stated at the outset, A denotes --CH 2 --C(R6)R7--CH--,
  • R6 denotes aryl
  • R7 denotes aryl, aryl having the meaning stated at the outset, and the salts of these compounds, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene and R6 and R7 denote phenyl.
  • Embodiment c can be characterised by the following formula Ic ##STR9## wherein the substituents and symbols have the meanings stated for embodiment c.
  • R1 denotes methyl or ethyl
  • R2 denotes methyl or ethyl
  • R3 denotes methyl or ethyl
  • E denotes ethylene or propylene
  • R6 denotes phenyl or 4-methoxyphenyl
  • R7 denotes phenyl or 4-methoxyphenyl
  • Particularly preferred compounds of embodiment c are those of the formula Ic, wherein
  • Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl
  • R1 denotes methyl
  • R2 denotes methyl
  • R3 denotes methyl or ethyl
  • E denotes ethylene or propylene
  • R6 denotes phenyl
  • R7 denotes phenyl
  • the invention furthermore relates to a process for the preparation of the compounds of the formula I ##STR10## wherein Cy represents a cyclic radical of the formula ##STR11## in which Y denotes oxygen (O), sulphur (S), vinylene (--CH ⁇ CH--), azomethine or a group of the formula ##STR12## R1 and R2 are identical or different and denote hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl,
  • R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, together methylenedioxy, amino or mono or di-1-4C-alkylamino,
  • E denotes straight-chain or branched 2-5C-alkylene which can be substituted by 1-4C-alkoxy or aryl,
  • A denotes --CH 2 --C(R6)R7--CH 2 -- or --CH 2 --NR8--CH 2 --,
  • R6 denotes hydrogen (H) or aryl
  • R7 denotes aryl or arylcarbonyl
  • R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2 4C-alkenylcarbonyl, aryl representing a ring of the formula ##STR13## wherein R9 and R10 are identical or different and denote hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl or trifluoromethyl, and
  • heteroaryl represents a 5-membered or 6-membered heterocyclic radical having one or two identical or different heteroatoms from the group consisting of oxygen (O), sulphur (S) or nitrogen (N), which heterocyclic radical is unsaturated or partially or completely saturated and which may carry one or two substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl and cyano, and their salts.
  • the process is characterised in that pure enantiomeric dihydropyridinecarboxylic acids which are protected at N and are of the formula II ##STR14## wherein R1, R2, R3 and Cy have the above-mentioned meanings and SG represents a protective group, are reacted with an omega-dihaloalkane Hal-E-Hal, wherein Hal denotes halogen and E has the above-mentioned meaning, and, after elimination of the protective group SG, the resulting haloalkyl ester III ##STR15## is reacted with an amine of the formula IV or a salt thereof ##STR16## to give the end product I, and, if desired, salts of the compound I which are subsequently obtained are converted into the free bases or the compounds I are converted into their salts.
  • the reaction of II with omega-dihaloalkanes is preferably carried out under basic conditions in the presence of a phase-transfer catalyst.
  • 1,2-Dihaloethanes and 1,3-dihalopropanes in particular 1,2-dibromomethane and 1,3-dibromopropane, may be mentioned as preferred omega-dihaloalkanes.
  • onium salts such as, for example, tetrabutylammonium bromide or benzyltriethylammonium bromide
  • crown ethers such as dibenzo-[18]crown-6, dicyclohexyl-[18]-crown-6 and in particular [18]-crown-6, may be mentioned as phase transfer catalysts.
  • the bases used which are employed at least in a molar ratio, preferably in excess, are inorganic bases, such as alkali metal hydroxides (for example sodium hydroxide or potassium hydroxide) or in particular alkali metal carbonates (for example sodium carbonate or preferably potassium carbonate).
  • alkali metal hydroxides for example sodium hydroxide or potassium hydroxide
  • alkali metal carbonates for example sodium carbonate or preferably potassium carbonate.
  • the reaction is carried out (depending on the type of phase transfer catalyst and the base used) in water-containing or anhydrous organic solvents, or in a mixture of water and an organic solvent which is immiscible or scarcely miscible with water.
  • the mixtures of water with chloroform, dichloromethane or benzene may be mentioned as examples of water/solvent mixtures.
  • Dichloromethane, acetonitrile and acetone may be mentioned as examples of water-containing or anhydrous solvents.
  • reaction temperature in the reaction II with dihaloalkanes depends on the remaining reaction conditions, as a rule temperatures between 20° C. and the boiling point of the solvent used being preferred.
  • Particularly suitable protective groups are those groups which can be introduced readily, and in high yields, into the precursor from which the compound II is derived, which do not undergo any side reactions during the reaction of II with dihaloalkanes and which can be eliminated again readily at the end.
  • Alkoxymethyl groups or benzyloxymethyl groups, in particular the ethoxymethyl group may be mentioned as examples of preferred protective groups SG.
  • Elimination of the protective group is carried out in an acidic medium, for example in 1 N hydrochloric acid or, preferably, in anhydrous formic acid, under reaction conditions familiar to the skilled worker. According to the invention, the protective group can also be eliminated after the reaction with the amine IV.
  • reaction of the haloalkyl esters 111 with amines IV is carried out in a manner familiar to the skilled worker for the reaction of alkyl halides and secondary amines.
  • the reaction is carried out in suitable preferably inert organic solvents in the presence of water or without water.
  • suitable preferably inert organic solvents include ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether; ketones, such as acetone or ethyl methyl ketone aromatic hydrocarbons, such as xylene or toluene; or chlorinated hydrocarbons, such as methylene chloride chloroform, tetrachloroethylene or dichloroethane; or polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide.
  • ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether
  • ketones such as acetone or ethyl methyl ketone aromatic hydrocarbons, such as xylene or
  • reaction temperatures can be varied within a wide range, depending on the reactivity of educts.
  • the reaction is carried out at temperatures between 20° C. and 150° C., preferably between 20° C. and 100° C., in particular at the boiling point of the solvent used.
  • the process can be carried out under atmospheric pressure or under elevated pressure, the procedure under atmospheric pressure being the usual one.
  • the reaction is carried out in the presence of a base (for example an inorganic carbonate, such as potassium carbonate) or with the use of an excess of amine IV.
  • a base for example an inorganic carbonate, such as potassium carbonate
  • the resulting compounds I according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallising the resulting residue from a suitable solvent or subjecting it to one of the conventional purification methods, such as, for example, column chromatography over a suitable carrier.
  • Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol or isopropanol) or an open-chain or cyclic ether, such as dioxane or tetrahydrofuran, which contains the desired acid, or to which the desired acid is subsequently added.
  • the salts are isolated by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporation of the solvent.
  • Salts obtained can be converted into the free bases by adding an alkali, for example aqueous ammonia solution, and the said bases can in turn be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.
  • an alkali for example aqueous ammonia solution
  • Embodiments of the process are those in which the substituents and symbols have the meanings stated for the compounds of embodiments a, b and c.
  • Processes to be singled out and preferred and particularly preferred processes are those in which the substituents and symbols have the meanings stated for the compounds to be singled out and preferred and particularly preferred compounds.
  • the compound prepared according to the invention is described by the following formula I * : ##STR17##
  • the process is characterised in that an N-protected dihydropyridinecarboxylic acid of the formula II * ##STR18## is reacted with 1,3-dibromopropane and, after elimination of the protective group SG, the resulting bromopropyl ester III * ##STR19## is reacted with diphenylpiperidine or a salt thereof to give the end product I * , and if desired, a resulting salt of compound I * is converted into the free base or the compound I * is converted into a salt.
  • the process according to the invention can likewise be used for the preparation of 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and its salts, by starting from the optical antipode of compound II * .
  • Particularly suitable deprotonating agents are agents for which the acidity of the proton on the nitrogen is sufficiently high to achieve anion formation.
  • organometallic compounds such as, for example, butyllithium
  • metal hydrides in particular sodium hydride
  • the leaving group X of the compound SG-X is a group which is readily eliminated in the reaction of SG-X with the deprotonated V. If the protective group SG is an alkoxymethyl group, X is preferably a halogen atom, in particular a chlorine atom.
  • the deprotonation and subsequent introduction of the protective group is carried out in inert anhydrous solvents, as are suitable for use with strong deprotonating agents.
  • Open-chain or cyclic ethers such as diethyl ether, dioxane or tetrahydrofuran may be mentioned as examples.
  • the reaction is preferably carried out under mild reaction conditions at temperatures of about or below O° C.
  • acceptor radicals in the further reaction are radicals which can have a mesomeric electron-attracting effect.
  • the nitro group or the azido group, preferably the nitrile group or a substituted sulphonyl group, may be mentioned as examples.
  • Halogen exchange in the N-protected haloethyl ester of the formula VI is preferably carried out by reaction with salts whose anions are capable of acting as covalently bonded acceptor substitutes.
  • a preferred reaction is the reaction with inorganic cyanides, in particular with potassium cyanide or sodium cyanide, or the reaction with alkali metal sulphinates, in particular with sodium 4-toluenesulphinate, if desired with the addition of catalytic amounts of a quaternary ammonium salt, such as, for example, tetrabutylammonium cyanide or benzyltriethylammonium chloride, in inert, preferably aprotic, polar solvents, such as, for example, acetone, dimethyl sulphoxide or dimethylformamide, at temperatures which are preferably between 0° C. and 50° C.
  • Cinchonidine and cinchonine may be mentioned in particular as pure enantiomeric, optically active bases.
  • haloethyl esters V used as starting compounds are disclosed, for example, in German Offenlegungsschrift 2,847,237.
  • the mother liquor is evaporated to dryness in vacuo, the residue is dissolved in 2 l of chloroform, 1 l of water is added while stirring vigorously and a stable of 2 to 3 is then obtained by the dropwise addition of 2 N hydrochloric acid.
  • the phases are separated and the organic phase is extracted by shaking with 0.01 N hydrochloric acid until cinchonidine is no longer detectable (thin-layer chromatography) and is washed with water and dried. After the solvent has been distilled off in vacuo the residue is dried under high vacuum and 85.6 g thereof are dissolved together with 54.5 g of cinchonine in about 2.4 1 of boiling ethanol.
  • Example D Analogously to Example D, 14.3 g of the title compound of m.p. 104°-106° C. (from methanol) are obtained from 19.1 g of 3-(2-bromoethyl) 5-methyl ( ⁇ )-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, 1.64 g of sodium hydride (80% in liquid paraffin), 4.75 g of chloromethyl ethyl ether and twice 50 ml of anhydrous tetrahydrofuran.
  • the pH is adjusted to 3 by the dropwise addition of 2 N hydrochloric acid solution while cooling with ice.
  • the precipitate which separates out during this procedure is filtered off under suction, washed neutral with water and dried. For purification, it is boiled with 90 ml of ethanol, cooled, filtered off under suction and washed with cold ethanol. Following drying, 37.5 g of the title compound of m.p. 181°-182° C. (decomp.) are obtained.
  • the filtrate is evaporated in a rotary evaporator under a slight vacuum, after which the excess 1,3-dibromopropane is distilled off at 0.02 mbar (bath temperature up to 45° C.). 690 ml of concentrated formic acid are poured over the oily residue after cooling with ice, after which stirring is carried out at room temperature until a clear solution has formed (about 15 min). The formic acid is distilled off in vacuo. After 200 ml portions of toluene have been added twice and distilled off twice, the residue is dissolved in 900 ml of dichloromethane. The solution is stirred thoroughly with sodium bicarbonate solution, washed with water, dried over sodium sulphate and evaporated in vacuo.
  • the pure enantiomeric compounds of the formula I prepared by the process according to the invention, and their salts, have valuable properties which make them industrially useful. They are, for example, effective vasodilators having therapeutic properties against coronary diseases.
  • the pharmacological activity of the compounds according to the invention, which is coupled with low toxicity, is evident, for example, in a slow, pronounced and long-lasting lowering of blood pressure.
  • the compounds according to the invention have an inhibitory effect on calcium influx and promote the flow of potassium out of cells, relax smooth muscle, dilate peripheral, coronary, cerebral and renal vessels and have salidiuretic, antithrombotic, antiarteriosclerotic and advantageous haemorheological properties.
  • the stress due to their less efficacious isostereomers, some of which may even have the opposite action or more pronounced side effects, is substantially reduced.
  • the enantiomers which are less efficacious in the abovementioned main (antihypertensive) action can be used for other therapeutic purposes, which were previously not accessible to this class of substances--owing to the main action predominating in the racemates.
  • the following may be mentioned as examples of advantageous properties of the compound of I: the extent of lowering of blood pressure, the good controllability of the lowering of blood pressure, the surprisingly small, and for repeated administration vanishing, increase in heart rate, the excellent bioavailability, the high therapeutic index, the lack of central side effects, the lack of kinetic interactions with other substances, the absence of development of tolerance, the well balanced physical properties and the high stability.
  • the excellent efficacy of the compounds according to the invention, of the formula I, and their salts permit their use in human medicine, examples of their indications being primary (essential) and secondary, arterial and pulmonal hypertensions of all severity levels, coronary heart diseases (coronary insufficiency, angina pectoras, myocardial infarction, etc.), peripheral and cerebral circulatory disorders (stroke, temporary cerebral blood-flow disturbances, migraine, giddiness, narrowing of renal arteries, etc.), hypertrophic cardiomyopathy, cardiac insufficiency, disorders due to increased water retention and sodium retention and disorders due to an increased influx of calcium, such as, for example, spasms of organs containing smooth muscle (respiratory tract, gastrointestinal tract, urogenital tract, etc.) and arrhythmia, arteriosclerosis and cell damage of various origins (for example hypoxia).
  • coronary heart diseases coronary insufficiency, angina pectoras, myocardial infarction, etc.
  • the invention therefore also relates to a method for the treatment of mammals, in particular humans, suffering from one of the above-mentioned disorders.
  • the method is characterised in that the suffering individual is administered a therapeutically effect and pharmacologically acceptable amount of one or more compounds of the formula I.
  • the invention furthermore relates to compounds of the formula I for use in the treatment of the stated disorders.
  • the invention also relates to the use of the compounds of the formula I for the preparation of medicaments which are used for the treatment of the stated disorders.
  • the invention furthermore relates to medicaments which contain one or more compounds of the general formula I.
  • the medicaments are prepared by processes known per se and familiar to the skilled worker.
  • auxiliaries are suitable for the desired drug formulations.
  • auxiliaries are suitable for the desired drug formulations.
  • solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavourings, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example cyclodextrins).
  • the active ingredients may be administered orally, rectally, by inhalation or parenterally (in particular perlingually, intravenously or percutaneously).
  • parenteral treatment similar or (in particular in the case of intravenous administration of the active ingredient) as a rule lower doses may be used.
  • a low dose is administered at the beginning of the treatment, after which higher doses are slowly introduced. After the desired therapeutic success has been attained, the dose is returned to a lower level.
  • the pharmaceutical formulations may also contain one or more other pharmacologically active constituents of other groups of medicaments, such as other vasodilators, antihypertensive agents, alpha-1-receptor blockers, alpha-2-receptor stimulators, beta-1-receptor blockers, beta-2-receptor stimulators.
  • other vasodilators such as other vasodilators, antihypertensive agents, alpha-1-receptor blockers, alpha-2-receptor stimulators, beta-1-receptor blockers, beta-2-receptor stimulators.
  • ACE inhibitors nitro compounds, cardio tonic agents, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergic agents, methylxanthines, antiarrhythmics, antihistamines, dopamine stimulators, serotonine receptor blockers, etc., such as nifedipine dihydralazine prazosine, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, rauwolfia total alkaloids, acetylsalicylic acid, bezafibrate, warfarin, atropine, theophy
  • the antihypertensive activity of the compounds according to the invention can be demonstrated in the model of the spontaneously hypertensive rat.
  • the compounds mentioned below are administered in the stated doses, on four successive days, to 6 male rats (strain SHR/N/Ibm/Bm, 250-350 g) with genetic high blood pressure (systolic high blood pressure >180 mmHg), once daily by means of a stomach tube.
  • the blood pressure is measured in each case 6 and, if necessary. 2 or 24 hours after administration of the substance.
  • the blood pressure measurement is carried out in a heated chamber at 36° C. in order to achieve better flow through the caudal artery.
  • the animals are placed in perforated metal cages and measurements are carried out 20-40 min after the beginning of heating.
  • an annula collar with an inflatable rubber membrane for suppressing blood flow and an annula piezocrystalline pick-up for detecting the pulse waves are pushed onto the tail.
  • the collar pressure is reduced continuously. The return of the pulse waves when the pressure is let down is detected automatically as systolic blood pressure and is printed out (Buhler, R. et.
  • the animals are trained for 14 days before testing of the substance.
  • preliminary blood pressure values are measured.
  • Groups of animals which receive the substance are tested against a control group.
  • the compounds investigated are denoted by serial numbers which correspond to the particular example numbers.
  • Table I shows the percentage lowering of blood pressure (BP) after oral administration in the rat for typical compounds according to the invention.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Enantiomerically-pure dihydropyridines of formula I ##STR1## are effective vasodilators useful for treating coronary diseases. They have particularly advantageous properties with regard to extent and controllability of blood pressure lowering, a surprisingly small (and for repeated administration--vanishing) increase in heart rate, excellent bioavailability, high therapeutic index, lack of central side effects, lack of kinetic interactions with other substances, absence of tolerance development, well-balanced physical properties and high stability. A new process for preparing these compounds is also presented.

Description

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel enantiomers processes for their preparation, their use and medicaments which contain them. The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments.
1. Known Prior Art
It is known that certain 1,4-dihydropyridine derivatives substituted in the 4-position have pharmacologically useful properties. It is also known that these 1,4-dihydropyridine derivatives, provided that they are differently (asymmetrically) substituted in positions 2 and 6 and/or in positions 3 and 5 - have a centre of chirality in position 4. It is also known that the pharmacological properties of the 1,4-dihydropyridines can be influenced by the absolute configuration in the 4-position. Because of these different pharmacological properties, various attempts have already been made to prepare pure 1,4-dihydropyridine enantiomers [see, for example, German Offenlegungsschrift 2,935,451, German Offenlegungsschrift 3,320,616, EP-A2 0166296, Shibaruma et al. Chem. Pharm. Bull. 28, 2809 (1980)]. However, either the known processes cannot be used to prepare all possible enantiomers of known 1,4-dihydropyridines or these processes give the pure 1,4-dihydropyridine enantiomers only in low yields or in insufficient purity.
2. Description of the Invention
Surprisingly, a novel process for the preparation of pure, optically active 1,4-dihydropyridine enantiomers has now been found, which gives the desired enantiomers in good yield and high purity. This process can be used for the preparation of novel enantiomers of the known 1,4-dihydropyridines.
The invention thus relates firstly to pure dihydropyridine enantiomers of the formula I ##STR2## wherein Cy represents a cyclic radical of the formula ##STR3## in which Y denotes oxygen (O), sulphur (S), vinylene (--CH═CH--), azomethine (--CH═N--) or a group of the formula ##STR4## R1 and R2 are identical or different and denote hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,
R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl,
R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl or 2-5C-acyl or together denote methylenedioxy, or denote amino or mono- or di-1-4C-alkylamino,
E denotes straight-chain or branched 2-5C-alkylene which may be substituted by 1-4C-alkoxy or aryl,
A denotes --CH2 --C(R6)R7--CH2 -- or --CH2 --NR8--CH2 --,
R6 denotes hydrogen (H) or aryl and
R7 denotes aryl or arylcarbonyl,
R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, aryl representing a ring of the formula ##STR5## wherein R9 and R10 are identical or different and have the meaning of hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl or trifluoromethyl, and heteroaryl represents a 5-membered or 6-membered heterocylic radical having one heteroatom or two identical or different heteroatoms from the group consisting of oxygen (O), sulphur (S) or nitrogen (N), which is unsaturated or partially or completely saturated and which may carry one or two substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl or cyano, and the salts of these compounds, except for the (S)-enantiomer of the compound in which Cy has the meaning of 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene, A represents CH2 --C(R6)R7--CH2 and R6 and R7 denote phenyl.
1-6C-Alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl or, in particular, ethyl or methyl radical.
3-7C-Alkoxyalkyl represents, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or, in particular, methoxyethyl radical.
According to the invention, halogen denotes bromine, fluorine and, in particular, chlorine.
1-4C-Alkyl is straight-chain or branched and means, for example, a butyl, isobutyl, sec-butyl, tert-butyl propyl, isopropyl, ethyl or, in particular methyl radical.
1-4C-Alkoxy contains, in addition to the oxygen atom, one of the above-mentioned 1-4C-alkyl radicals. The methoxy radical and the ethoxy radical are preferred.
1-4C-Alkoxy which is completely or partially substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, in particular, difluoromethoxy.
1-4C-Alkoxycarbonyl contains in addition to the carbonyl group, one of the above-mentioned 1-4C-alkoxy radicals. The methoxycarbonyl radical and the ethoxycarbonyl radical are preferred.
2-5C-Acyl contains in addition to the carbonyl group, one of the above-mentioned 1-4C-alkyl radicals. The acetyl radical is preferred.
Mono- or di-1-4C-alkylamino contains in addition to the nitrogen atom, one or two of the above-mentioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred, in particular dimethyl-, diethyl- or diisopropylamino.
Straight-chain or branched 2-5C-alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and in particular ethylene or propylene.
Aryl represents phenyl which is substituted by R9 and R10. The following radicals may be mentioned as examples of preferred aryl radicals: phenyl, 4-methoxyphenyl 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 3,6-dichlorophenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,4-methylenedioxyphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
Aryl-1-4C-alkyl represents one 1-4C-alkyl which is substituted by aryl. The following radicals may be mentioned as examples of preferred aryl-1-4C-alkyl radicals: 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 1-phenylethyl, 2-phenylethyl, 3-chlorobenzyl, 2.5-dimethylbenzyl, 4-fluorobenzyl, 3-methylbenzyl and in particular benzyl.
Aryl-2-4C-alkenyl and aryl-2-4C-alkynyl represent alkenyl and alkynyl radicals having 2 to 4 carbon atoms, which are substituted by aryl. The 3-phenyl-2-propenyl radical and the 3-phenyl-2-propynyl radical may be mentioned as examples.
Arylcarbonyl represents a carbonyl group which is substituted by aryl. The 4-chlorophenylcarbonyl, 2-hydroxyphenylcarbonyl (salicyloyl), the 4-hydroxyphenylcarbonyl and in particular the 4-fluorophenylcarbonyl and the benzoyl group may be mentioned as examples of preferred arylcarbonyl groups.
The following radicals may be mentioned as examples of preferred (substituted) heteroaryl radicals: furyl, in particular 2-furyl, thienyl, in particular 2-thienyl, pyrimidyl, in particular 2-pyrimidyl, 3-cyano-2-pyridyl, thiazolyl, in particular 2-thiazolyl, and pyridyl, in particular 3-pyridyl and preferably 2-pyridyl.
Heteroarylcarbonyl represents a carbonyl group which is substituted by heteroaryl. The nicotinoyl radical and the 2-furoyl radical may be mentioned as examples of preferred heteroarylcarbonyl radicals.
Heteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl. Heteroaryl-1-4C-alkyl is, for example, 2-(2-pyridyl)-ethyl.
Diaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two aryl radicals. Diaryl-1-4C-alkyl is, in particular diphenylmethyl (benzhydryl) or substituted benzhydryl, such as, for example, 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl, 4,4'-dimethoxyhydryl or 4,4'-dichlorobenzhydryl.
Heteroaryl-aryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl and aryl. Diheteroaryl-aryl-1-4C-alkyl is, for example, 2-pyridylphenylmethyl.
Diheteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two heteroaryl radicals. Diheteroaryl-1-4C-alkyl is, for example, dipyrid-2-ylmethyl.
Arylsulphonyl represents a sulphonyl group which is substituted by aryl. The 4-chlorophenylsulphonyl radical and the 4-methoxyphenylsulphonyl radical may be mentioned as examples of preferred arylsulphonyl radicals.
The 2-phenylpropionyl radical may be mentioned as an example of an aryl-1-4C-alkylcarbonyl radical. The cinnamoyl radical may be mentioned as an example of an aryl-2-4C-alkenylcarbonyl radical.
Suitable salts are all salts with acids. The pharmacologically acceptable salts of the inorganic or organic acids usually used in the pharmaceutical industry may be mentioned in particular. Pharmacologically unacceptable salts, which may initially be obtained as products of the process, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the skilled worker. Examples of suitable solvents of this type are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, metembonate, stearate, tosylate 2-hydroxy-3-naphtoate, 3-hydroxy-2-naphthoate or mesylate, as well as salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrynic acid, tienilic acid or 4-chlorosulphamoylbenzoic acid.
The invention thus relates firstly to a novel pure 1,4-dihydropyridine enantiomer of the formula I which can be isolated or has been isolated for the first time.
The invention preferably relates to pure enantiomeric compounds of the formula I,
wherein
Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl,
R1 and R2 are identical or different and denote 1-4C-alkyl,
R3 denotes 1-4C-alkyl,
E denotes ethylene or propylene.
A denotes --CH2 --C(R6)R7--CH2 -- or --CH2 --NR8--CH--,
R6 denotes hydrogen (H) or phenyl,
R7 denotes phenyl and
R8 denotes aryl or benzhydryl, aryl representing a ring of the formula ##STR6## wherein R9 and R10 are identical or different and denote hydrogen (H), 1-4C-alkoxy or halogen,
and the salts of these compounds, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene, A represents CH2 --C(R6)R7--CH2 and R6 and R7 denote phenyl.
An embodiment (embodiment a) of the invention comprises pure enantiomeric compounds of the formula 1, wherein Cy, R1, R2, R3, R4, R5 and E have the meanings stated at the outset,
A denotes --CH2 --C(R6)R7--CH--,
R6 denotes hydrogen (H) and
R7 denotes aryl or arylcarbonyl aryl having the meaning stated at the outset, and the salts of these compounds.
The embodiment a can be characterised by the following formula Ia ##STR7## wherein the substituents and symbols have the meanings stated for embodiment a.
Compounds of embodiment a which are to be singled out are those of the formula Ia, wherein
Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene,
R6 denotes hydrogen and
R7 denotes phenyl, benzoyl, 4-chlorobenzoyl or 4-fluorobenzoyl, and their salts.
Particularly preferred compounds of embodiment a are those of the formula Ia, wherein
Cy denotes 3-nitrophenyl,
R1 denotes methyl,
R2 denotes methyl,
R3 denotes methyl,
E denotes ethylene or propylene,
R6 denotes hydrogen and
R7 denotes phenyl, and their salts.
The following may be mentioned as examples of particularly noteworthy compounds of embodiment a:
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(4-fluorobenzoyl)-piperid-1-yl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(4-fluorobenzoyl)-piperid-1-yl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenylpiperid-1-yl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(4-fluorobenzoyl)-piperid-1-yl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(4-fluorobenzoyl)-piperid-1-yl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, and their salts.
A further embodiment (embodiment b) of the invention comprises pure enantiomeric compounds of the formula I, wherein Cy, R1, R2, R3, R4, R5 and E have the meanings stated at the outset,
A denotes --CH2 --NR8--CH2 --,
R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, aryl and heteroaryl having the meanings stated at the outset,
and the salts of these compounds.
Embodiment b can be characterised by the following formula Ib ##STR8## wherein the substituents and the symbols have the meanings stated for embodiment b.
Compounds of embodiment b which are to be singled out are those of the formula Ib, wherein
Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene and
R8 denotes phenyl, 2-methoxyphenyl. 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-pyridyl or benzhydryl, and their salts.
Particularly preferred compounds of embodiment b are those of the formula Ib, wherein
Cy denotes 3-nitrophenyl,
R1 denotes methyl,
R2 denotes methyl,
R3 denotes methyl,
E denotes ethylene or propylene and
R8 denotes phenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl or benzhydryl,
and their salts.
The following may be mentioned as examples of particularly noteworthy compounds of embodiment b:
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenyl-1-piperazinyl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenyl-1-piperazinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-(2-[4-(2-pyridyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl5-[2-(4-benzhydryl)-1-piperazinyl]-ethyl (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl)-1-piperazinyl]-propyl(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3-methoxyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(3-methoxyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3,4-methylenedixoyphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(3,4-methylenedixoyphenyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-tolyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-tolyl)-1-piperazinyl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2,4-dimethylphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl5-{2-[4-(2,4-dimethylphenyl)-1-piperazinyl]-ethyl}(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-(3-[4-(2,6-dimethylphenyl)-1-piperazinyl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2,6-dimethylphenyl)-1-piperazinyl]-ethyl}(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-chlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl}-pyridine-3,5-dicarboxylate
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl](-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl](-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-phenyl-1-piperazinyl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-phenyl-1-piperazinyl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4-benzhydryl)-1-piperazinyl]-ethyl (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4-benzhydryl)-1-piperazinyl]-propyl(-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3-ethoxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3-methoxyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(3-methoxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(3,4-methylenedixoyphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-(2-[4-(3,4-methylenedioxyphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2-tolyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2-tolyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2,4-dimethylphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2,4-dimethylphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4-(2,6-dimethylphenyl)-1-piperazinyl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4-(2,6-dimethylphenyl)-1-piperazinyl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, and their salts.
A further embodiment (embodiment c) of the invention comprises pure enantiomeric compounds of the formula I, wherein
Cy, R1 R2, R3, R4, R5 and E have the meanings stated at the outset, A denotes --CH2 --C(R6)R7--CH--,
R6 denotes aryl and
R7 denotes aryl, aryl having the meaning stated at the outset, and the salts of these compounds, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene and R6 and R7 denote phenyl.
Embodiment c can be characterised by the following formula Ic ##STR9## wherein the substituents and symbols have the meanings stated for embodiment c.
Compounds of embodiment c to be singled out are those of the formula Ic, wherein Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene,
R6 denotes phenyl or 4-methoxyphenyl and
R7 denotes phenyl or 4-methoxyphenyl,
and their salts, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene and R6 and R7 denote phenyl.
Particularly preferred compounds of embodiment c are those of the formula Ic, wherein
Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl,
R1 denotes methyl,
R2 denotes methyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene,
R6 denotes phenyl and
R7 denotes phenyl,
and their salts, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene and R6 and R7 denote phenyl.
The following may be mentioned as examples of particularly noteworthy compounds of embodiment c:
3-methyl 5-{2-[4,4-di-(4-methoxyphenyl)-piperid-1-yl]-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4,4-di-(4-methoxyphenyl)-piperid-1-yl]-propyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-2-(4,4-diphenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{2-[4,4-di-(4-methoxyphenyl)-piperid-1-yl]-ethyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-{3-[4,4-di-(4-methoxyphenyl)-piperid-1-yl]-propyl} (-)-1,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl](-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[2-(4,4-diphenylpiperid-1-yl)-ethyl](-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate
3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2.3-dichlorophenyl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(2,1,3-benzoxdiazol-4-yl)-pyridine-3,5-dicarboxylate,
3-methyl 5-[3-(4,4-diphenyl-1-piperidinyl)-propyl](-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, and their salts.
Of particular interest, and therefore a preferred subject of the invention, are the enantiomers which, in the 4-position of the dihydropyridine, have the same configuration as the (-)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonidine salt which can be used as a precursor and which rotates linearly polarised light of wavelength 589 nm through [α]22 D =-63.4° (c=1, chloroform).
The invention furthermore relates to a process for the preparation of the compounds of the formula I ##STR10## wherein Cy represents a cyclic radical of the formula ##STR11## in which Y denotes oxygen (O), sulphur (S), vinylene (--CH═CH--), azomethine or a group of the formula ##STR12## R1 and R2 are identical or different and denote hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl,
R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, together methylenedioxy, amino or mono or di-1-4C-alkylamino,
E denotes straight-chain or branched 2-5C-alkylene which can be substituted by 1-4C-alkoxy or aryl,
A denotes --CH2 --C(R6)R7--CH2 -- or --CH2 --NR8--CH2 --,
R6 denotes hydrogen (H) or aryl and
R7 denotes aryl or arylcarbonyl,
R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2 4C-alkenylcarbonyl, aryl representing a ring of the formula ##STR13## wherein R9 and R10 are identical or different and denote hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl or trifluoromethyl, and
heteroaryl represents a 5-membered or 6-membered heterocyclic radical having one or two identical or different heteroatoms from the group consisting of oxygen (O), sulphur (S) or nitrogen (N), which heterocyclic radical is unsaturated or partially or completely saturated and which may carry one or two substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl and cyano, and their salts.
The process is characterised in that pure enantiomeric dihydropyridinecarboxylic acids which are protected at N and are of the formula II ##STR14## wherein R1, R2, R3 and Cy have the above-mentioned meanings and SG represents a protective group, are reacted with an omega-dihaloalkane Hal-E-Hal, wherein Hal denotes halogen and E has the above-mentioned meaning, and, after elimination of the protective group SG, the resulting haloalkyl ester III ##STR15## is reacted with an amine of the formula IV or a salt thereof ##STR16## to give the end product I, and, if desired, salts of the compound I which are subsequently obtained are converted into the free bases or the compounds I are converted into their salts. The reaction of II with omega-dihaloalkanes is preferably carried out under basic conditions in the presence of a phase-transfer catalyst.
1,2-Dihaloethanes and 1,3-dihalopropanes, in particular 1,2-dibromomethane and 1,3-dibromopropane, may be mentioned as preferred omega-dihaloalkanes.
In addition to onium salts, such as, for example, tetrabutylammonium bromide or benzyltriethylammonium bromide, in particular crown ethers, such as dibenzo-[18]crown-6, dicyclohexyl-[18]-crown-6 and in particular [18]-crown-6, may be mentioned as phase transfer catalysts.
The bases used, which are employed at least in a molar ratio, preferably in excess, are inorganic bases, such as alkali metal hydroxides (for example sodium hydroxide or potassium hydroxide) or in particular alkali metal carbonates (for example sodium carbonate or preferably potassium carbonate). When the reaction is carried out in an anhydrous solvent, the hydroxides or carbonates used are preferably employed in finely pulverulent form.
The reaction is carried out (depending on the type of phase transfer catalyst and the base used) in water-containing or anhydrous organic solvents, or in a mixture of water and an organic solvent which is immiscible or scarcely miscible with water. The mixtures of water with chloroform, dichloromethane or benzene may be mentioned as examples of water/solvent mixtures. Dichloromethane, acetonitrile and acetone may be mentioned as examples of water-containing or anhydrous solvents.
The solvents, bases and phase transfer catalysts mentioned in the Examples are only an illustrative selection. From his technical knowledge, the skilled worker is familiar with further suitable combinations of solvents, bases and phase transfer catalysts.
The choice of reaction temperature in the reaction II with dihaloalkanes depends on the remaining reaction conditions, as a rule temperatures between 20° C. and the boiling point of the solvent used being preferred.
Particularly suitable protective groups are those groups which can be introduced readily, and in high yields, into the precursor from which the compound II is derived, which do not undergo any side reactions during the reaction of II with dihaloalkanes and which can be eliminated again readily at the end. Alkoxymethyl groups or benzyloxymethyl groups, in particular the ethoxymethyl group, may be mentioned as examples of preferred protective groups SG. Elimination of the protective group is carried out in an acidic medium, for example in 1 N hydrochloric acid or, preferably, in anhydrous formic acid, under reaction conditions familiar to the skilled worker. According to the invention, the protective group can also be eliminated after the reaction with the amine IV.
The reaction of the haloalkyl esters 111 with amines IV is carried out in a manner familiar to the skilled worker for the reaction of alkyl halides and secondary amines.
The reaction is carried out in suitable preferably inert organic solvents in the presence of water or without water. Examples which may be mentioned are ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether; ketones, such as acetone or ethyl methyl ketone aromatic hydrocarbons, such as xylene or toluene; or chlorinated hydrocarbons, such as methylene chloride chloroform, tetrachloroethylene or dichloroethane; or polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide.
The reaction temperatures can be varied within a wide range, depending on the reactivity of educts. In general, the reaction is carried out at temperatures between 20° C. and 150° C., preferably between 20° C. and 100° C., in particular at the boiling point of the solvent used.
The process can be carried out under atmospheric pressure or under elevated pressure, the procedure under atmospheric pressure being the usual one. The reaction is carried out in the presence of a base (for example an inorganic carbonate, such as potassium carbonate) or with the use of an excess of amine IV.
The resulting compounds I according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallising the resulting residue from a suitable solvent or subjecting it to one of the conventional purification methods, such as, for example, column chromatography over a suitable carrier. Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol or isopropanol) or an open-chain or cyclic ether, such as dioxane or tetrahydrofuran, which contains the desired acid, or to which the desired acid is subsequently added.
The salts are isolated by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporation of the solvent.
Salts obtained can be converted into the free bases by adding an alkali, for example aqueous ammonia solution, and the said bases can in turn be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.
Embodiments of the process are those in which the substituents and symbols have the meanings stated for the compounds of embodiments a, b and c. Processes to be singled out and preferred and particularly preferred processes are those in which the substituents and symbols have the meanings stated for the compounds to be singled out and preferred and particularly preferred compounds.
Of particular importance in this context is the use of the process according to the invention for the preparation of that enantiomer of 3-methyl-5-[3-(4,4-diphenylpiperid-1-yl)-propyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate which rotates linearly polarised light of wavelength 589 nm in the (+) direction, that is to say of 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, and its salts, and of the corresponding (-)-enantiomer and its salts.
Without taking into account the absolute configuration in the 4-position of the 1,4-dihydropyridine, the compound prepared according to the invention is described by the following formula I* : ##STR17## In this case, the process is characterised in that an N-protected dihydropyridinecarboxylic acid of the formula II* ##STR18## is reacted with 1,3-dibromopropane and, after elimination of the protective group SG, the resulting bromopropyl ester III* ##STR19## is reacted with diphenylpiperidine or a salt thereof to give the end product I*, and if desired, a resulting salt of compound I* is converted into the free base or the compound I* is converted into a salt.
The process according to the invention can likewise be used for the preparation of 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and its salts, by starting from the optical antipode of compound II*.
Some of the pure enantiomeric compounds of the formula II or II* are known [Chem. Pharm. Bull. 28(9) 2809-2812 (1980)] and some are novel. They can be prepared in a known manner [Chem. Pharm. Bull. 28(9) 2809-2812 (1980)] or by a novel process.
The novel process is characterised in that the protective group SG is introduced into haloethyl esters of the formula V (Hal=chlorine, in particular bromine) ##STR20## Hal is exchanged for a nucleophile acting as an acceptor (=Akz) in the resulting N-protected haloethyl ester of the formula VI ##STR21## the acceptor ethyl radical is eliminated from the resulting acceptor ethyl ester of the formula VII ##STR22## under basic conditions and the resulting racemate of the compound II is resolved into the enantiomers.
To introduce the protective group SG, it is advantageous to adopt a procedure in which the haloethyl ester V is deprotonated in the 1-position and then reacted with a compound SG-X, where X represents a suitable leaving group.
Particularly suitable deprotonating agents are agents for which the acidity of the proton on the nitrogen is sufficiently high to achieve anion formation. In addition to organometallic compounds, such as, for example, butyllithium, metal hydrides, in particular sodium hydride, may be preferably mentioned. The leaving group X of the compound SG-X is a group which is readily eliminated in the reaction of SG-X with the deprotonated V. If the protective group SG is an alkoxymethyl group, X is preferably a halogen atom, in particular a chlorine atom.
The deprotonation and subsequent introduction of the protective group is carried out in inert anhydrous solvents, as are suitable for use with strong deprotonating agents. Open-chain or cyclic ethers, such as diethyl ether, dioxane or tetrahydrofuran may be mentioned as examples. The reaction is preferably carried out under mild reaction conditions at temperatures of about or below O° C.
Particularly suitable acceptor radicals in the further reaction are radicals which can have a mesomeric electron-attracting effect. The nitro group or the azido group, preferably the nitrile group or a substituted sulphonyl group, may be mentioned as examples.
Halogen exchange in the N-protected haloethyl ester of the formula VI is preferably carried out by reaction with salts whose anions are capable of acting as covalently bonded acceptor substitutes. A preferred reaction is the reaction with inorganic cyanides, in particular with potassium cyanide or sodium cyanide, or the reaction with alkali metal sulphinates, in particular with sodium 4-toluenesulphinate, if desired with the addition of catalytic amounts of a quaternary ammonium salt, such as, for example, tetrabutylammonium cyanide or benzyltriethylammonium chloride, in inert, preferably aprotic, polar solvents, such as, for example, acetone, dimethyl sulphoxide or dimethylformamide, at temperatures which are preferably between 0° C. and 50° C.
The elimination of the acceptor ethyl radical under basic conditions, which follows the halogen exchange is a reaction which is familiar to the skilled worker and is described in, for example. German Offenlegungsschrift 2,847,237. The compound II, which is initially obtained as a racemate, can be resolved into the enantiomers (+)-II and (-)-II with the aid of pure enantiomeric, optically active bases in a conventional manner via the diastereomeric salts [see, for example, Chem. Pharm. Bull. 23 2809 (1980)][1].
Cinchonidine and cinchonine may be mentioned in particular as pure enantiomeric, optically active bases.
The haloethyl esters V used as starting compounds are disclosed, for example, in German Offenlegungsschrift 2,847,237.
The preparation examples which follow are intended to illustrate the invention in detail without restricting it. Mp. denotes melting point, h represents hours, b.p. represents boiling point and decomp. denotes decomposition. Ether is understood as being diethyl ether.
EXAMPLES End Products 1. 3-Methyl 5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
3.7 g of 3-methyl 5-(3-bromopropyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.8g of 1-(2-methoxyphenyl)-piperazine semicarbonate and 3.4 g of potassium carbonate in a mixture of 35 ml of toluene and 10 ml of water are refluxed for 9 hours under a nitrogen atmosphere with vigorous stirring. After cooling, the phases are separated, and the organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. The residue is crystallised from ethyl acetate/diisopropyl ether. After filtration under suction, washing with diisopropyl ether and drying in vacuo, 3.4 g of the title compound of m.p. 139°-140° C. and [α]22 D =+16.9° (c=1, methanol) are obtained.
2. 3-Ethyl 5-[3-(4,4-diphenyl-1-piperidinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
2 g of (+)-5-ethoxycarbonyl-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid are dissolved in 25 ml of acetone, and 1.5 g of finely powdered potassium carbonate, 7.5 ml of 1,3-dibromopropane and a spatula tip of [18]crown-6 are added. The mixture is stirred vigorously for 20 h at room temperature, after which the solution is filtered off from the solid, the filtrate is evaporated in vacuo and the excess 1,3-dibromopropane is distilled off under high vacuum. 15 ml of concentrated formic acid are added to the residue while cooling with ice; stirring is then carried out at room temperature until a clear solution has formed (about 15-20 minutes). The formic acid is distilled off in vacuo, the residue is dissolved in 30 ml of dichloromethane and the solution is washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated again. The crystalline residue is triturated with diisopropyl ether, filtered off under suction, washed with diisopropyl ether and dried. 2.2 g are obtained and are heated at the boil, without further purification, with 1.32 g of 4,4-diphenylpiperidine hydrochloride and 2 g of potassium carbonate in a mixture of 20 ml of toluene and 4 ml of water for 30 h. After cooling, the phases are separated. The organic phase is washed twice with water and evaporated. The residue is chromatographed over a silica gel column using 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The residue is dissolved in dichloromethane, 2 ml of a saturated solution of hydrogen chloride in ether are added and the mixture is immediately evaporated in vacuo. Two portions of 20 ml of dichloromethane are distilled off, after which the residue is triturated with ether, filtered off under suction and dried. 2.65 g of the title compound which decomposes from 142° C. and has [α]22 D =+18.9° (c=1, methanol) are obtained.
3. 3-Methyl 5-3-(4,4-diphenylpiperid-1-yl)-propyl] (-)-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate hydrochloride
1.3 8 of (+)-4-(2,3-dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylic acid are dissolved in 15 ml of acetone, 1 g of finely powdered potassium carbonate, 5 ml of 1,3-dibromopropane and a spatula tip of [18]crown-6 are added and vigorous stirring is carried out for 20 h. The solution is filtered off under suction from the solid, the filtrate is evaporated in vacuo and the excess 1,3-dibromopropane is distilled off under high vacuum. 10 ml of concentrated formic acid are added to the residue while cooling with ice; stirring is then carried out at room temperature until a clear solution has formed (about 15-20 minutes). The formic acid is distilled off in vacuo, the residue is dissolved in 20 ml of dichloromethane and the solution is washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated down. The residue is dried under high vacuum. The solid foam (1.2 g) is heated at the boil, without further purification, with 0.68 g of 4,4-diphenylpiperidine hydrochloride and 1 g of potassium carbonate in a mixture of 15 ml of toluene and 5 ml of water for 21 h. After cooling, the phases are separated. The organic phase is washed twice with water and evaporated. The residue is chromatographed over a silica gel column using 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The remaining oil is dissolved in 20 ml of dichloromethane, 2 ml of a saturated solution of hydrogen chloride in ether are added to the solution and the mixture is immediately evaporated in vacuo. Two 20 ml portions of dichloromethane are distilled off, after which the residue is triturated with ether, filtered off under suction, washed with ether and dried. 1.3 g of the title compound which decomposes from 160° C. and has [α]22 D =-41.4° (c=1, methanol) are obtained.
4. 3-Methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
A mixture of 13 g of 3-methyl 5-(3-bromopropyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 7.85 g of 4,4-diphenylpiperidine hydrochloride and 12 g of potassium carbonate in 120 ml of toluene and 25 ml of water is refluxed for 14 h under a nitrogen atmosphere and with vigorous stirring. After cooling, the phases are separated; the organic phase is washed twice with water, dried over sodium sulphate and evaporated in vacuo. The oily residue is dissolved in 140 ml of dioxane, after which 2.3 ml of concentrated hydrochloric acid solution (12.5 M, d=1.19) are added and 20-25 ml of the solvent mixture are then distilled off in vacuo. On standing at room temperature, the product crystallises spontaneously or after trituration and is filtered off under suction after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80° C. 16 g of the title compound of m.p. 158°-160° C. and [α]22 D =+14.4° (c=1, methanol) are obtained.
5. 3-Methyl 5-[3-(4,4-diphenyl-1-piperidinyl)-propyl] (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
86.6 g of 3-methyl 5-(3-bromopropyl) (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 50 g of 4,4-diphenylpiperidine hydrochloride and 69 g of finely milled potassium carbonate are heated together in 300 ml of dimethylformamide for 5 h at 100° C. with vigorous stirring and under a nitrogen atmosphere. After cooling, 500 ml of ethyl acetate and 1 l of water are added in succession and the mixture is stirred thoroughly. After phase separation, the organic phase is washed 4 times with water, dried over sodium sulphate and evaporated in vacuo. The residue is dissolved in 1 l of dioxane and 15.2 ml of concentrated hydrochloric acid solution (12.5 M, d=1.19) are added to the cooled solution; about 200 ml of the solvent mixture are then distilled off in vacuo. On standing at room temperature, the product crystallises spontaneously or after seeding or trituration; it is filtered off under suction after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80°-100° C. For purification, the product is dissolved in dichloromethane. After the addition of 800 ml of dioxane, the dichloromethane is distilled off again. The product which has crystallised out after seeding and standing at room temperature for 16 hours is filtered off under suction, washed with dioxane and diisopropyl ether and dried at 100° C. 97 g of the title compound of m.p. 158°-160° C. and [α]22 436 =-39° (c=1, methanol) or [α]22 D =-14.4° (c=1. methanol) are obtained.
6. 3-Methyl 5-[2-(4,4-diphenyl-1-piperidinyl)-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
2.35 g of 3-methyl 5-(2-bromoethyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.46 g of 4,4-diphenylpiperidine hydrochloride and 1.55 g of finely powdered potassium carbonate in 15 ml of anhydrous dimethylformamide are stirred for 6 h at 80° C. After the mixture has cooled, 100 ml of water are added and the mixture is then extracted with ether. The ether phase is washed twice with water, dried over sodium sulphate and then evaporated in vacuo. The residue is chromatographed over a silica gel column using a 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The residue is dissolved in ether and 2 ml of a saturated solution of hydrogen chloride in ether are added to the solution, crystallisation occurring. The product is filtered off under suction, washed with ether and dried. 1.4 g of the title compound of m.p. 155°-158° C. (decomp.) and [α]22 D =+68.4° (c=1, methanol) are obtained.
7. 3-Methyl 5-[2-(4-phenyl-1-piperidinyl)-ethyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
Analogously to Example 6, 2.9 g of the title compound of m.p. 129°-131° C. (decomp.) and [α]21 D =+40.8° (c=1, methanol) are obtained from 5 g of 3-methyl-5-(2-bromoethyl)+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.9 g of 4-phenylpiperidine and 4.4 g of diisopropylethylamine after chromatography and crystallisation from 2-propanol.
8. 3-Methyl 5-[3-(4-phenyl-1-piperidinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
Analogously to Example 6, 3.4 g of the title compound which decomposes from 100° C. and has [α]21 D =+41.7° (c=1, methanol) are obtained from 5 g of 3-methyl-5-(3-bromopropyl) (+) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.9 g of 4-phenylpiperidine and 4.4 g of diisopropylethylamine.
9. 3-Methyl 5-{3-[4-(2-ethoxy-4-fluorophenyl)-1-piperazinyl]-propyl}(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
Analogously to Example 6, 2.1 g of the title compound of m.p. 150°-152° C. and [α]22 D =+14 4° (c=1, methanol) are obtained from 3 g of 3-methyl-5-bromopropyl (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 2 g of 1-(2-ethoxy-4-fluorophenyl)-piperazine dihydrochloride and 3.7 g of finely powdered potassium carbonate in 20 ml of absolute dimethylformamide after chromatography and crystallisation from 2-propanol.
10. 3-Methyl 5-[2-(4-benzhydryl-1-piperazinyl)-ethyl} (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate dihydrochloride
Analogously to Example 6, 3.2 g of the title compound which decomposes from 210° C. and has [α]21 D =+52.1° (c=1, methanol) are obtained from 4 g of 3-methyl-5-(2-bromoethyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 6.5 g of 1-benzhydrylpiperazine after chromatography and conversion into the dihydrochloride.
11. 3-Methyl 5-[3-(4-benzhydryl-1-piperazinyl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate dihdydrochloride
Analogously to Example 6, 4 g of the title compound which decomposes from 170° C. and has [α]22 D =+35.2° (c=1, methanol) are obtained from 4.5 g of 3-methyl-5-(3-bromopropyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 2,6 g of 1-benzhydrylpiperazine and 2.8 g of finely powdered potassium carbonate after chromatography and conversion into the dihydrochloride.
STARTING COMPOUNDS A. 3-Methyl 5-(3-bromopropyl}(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
36 g of (-)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonidine salt are dissolved in 250 ml of chloroform, 260 ml of 0.2 N hydrochloric acid solution are added and the mixture is stirred vigorously. By adding 2 N hydrochloric acid solution, the pH is adjusted to 2, after which the phases are separated. The organic phase is washed a total of 4 times with hydrochloric acid solution at pH 2 and then with water, dried over sodium sulphate and evaporated. The oily residue is dissolved in 200 ml of acetone. Thereafter, 16 g of finely powdered potassium carbonate, 80 ml of 1,3-dibromopropane and 0.5 g of [18]crown-6 are added. The mixture is stirred vigorously for 16 h at room temperature and then filtered under suction, and the filter cake is washed with acetone. The acetone is stripped off in a rotary evaporator under a slight vacuum and the excess 1,3-dibromopropane is distilled off at 0.02 mbar. 160 ml of concentrated formic acid is poured over the oily residue while cooling with ice; stirring is then carried out at room temperature until a clear solution is formed (about 15 minutes). The formic acid is distilled off in vacuo. After two 50 ml portions of toluene have been added and distilled off, the residue is dissolved in dichloromethane. The solution is stirred thoroughly with sodium bicarbonate solution (pH 8.5). The organic phase is dried over sodium sulphate and evaporated. The oily residue is then crystallised from methanol at room temperature. 18.9 g of the title compound of m.p. 112°-114° C. and [α]22 D =+13.8° (c=1, methanol) are obtained.
8. (-)-1-Ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonidine salt
229.7 g of (±)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid and 173.2 g of cinchonidine are dissolved in 2.4 l of ethanol at elevated temperatures. On slow cooling, the title compound crystallises out and, after standing at room temperature for 2 days, is filtered off under suction and washed with ethanol. Recrystallisation twice from ethanol gives 148 g of the title compound of m.p. 185°-185.5° C. and [α]22 D =-63.4° (c=1, chloroform). By working up the mother liquor from the first crystallisation, the corresponding (+)-enantiomer can be obtained:
The mother liquor is evaporated to dryness in vacuo, the residue is dissolved in 2 l of chloroform, 1 l of water is added while stirring vigorously and a stable of 2 to 3 is then obtained by the dropwise addition of 2 N hydrochloric acid. The phases are separated and the organic phase is extracted by shaking with 0.01 N hydrochloric acid until cinchonidine is no longer detectable (thin-layer chromatography) and is washed with water and dried. After the solvent has been distilled off in vacuo the residue is dried under high vacuum and 85.6 g thereof are dissolved together with 54.5 g of cinchonine in about 2.4 1 of boiling ethanol. The product which has crystallised out after standing for 3 days at room temperature is filtered off under suction, washed with ethanol and once again recrystallised from ethanol. 88.5 g of (+)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2 6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonine salt of m.p. 197°-198° C. and [α ]22 D =+101.5° (c=1, methanol) are obtained.
C. (±)-1-Ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid
(a) 195.5 g of 3-methyl 5-(2-bromoethyl) (±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate are dissolved in 900 ml of dimethylformamide, and 40.6 g of powdered sodium cyanide and 0.5 g of tetrabutylammonium cyanide are added. The mixture is stirred for 26 h at room temperature, a thick precipitate separating out after about 4 h, after which 200 ml of 2 N sodium hydroxide solution are added dropwise and stirring is continued for 5 h at room temperature. The mixture is stirred into 4.5 l of water and 2 N hydrochloric acid solution are added dropwise, while cooling and stirring vigorously, until the pH reaches 2.5. The product precipitated during this procedure is filtered off under suction rapidly, washed neutral with water, dried in the air overnight and then heated in 400 ml of ethanol on a steam bath (no solution). It is left to stand for 12 h at room temperature, then cooled, filtered off under suction and dried. 142 g of the title compound of m.p. 176°-176.5° C. (decomposition) are obtained.
(b) 5 g of 3-methyl 5-(2-bromoethyl) (±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate are dissolved in 35 ml of dimethylformamide, 3.55 g (20 mmol) of sodium 4-toluenesulphinate and 0.1 g of benzyltriethylammonium chloride are added and the mixture is stirred for 20 h at 20° C. 11 ml of 2 N sodium hydroxide solution are added, the mixture is stirred for 5 h at 20° C. and for a further 3 h at 80° C. and is cooled and then poured onto 120 ml of ice water. After the addition of acetic acid until a pH of 3.8 is obtained, stirring is carried out for 3 h in an ice bath, the solution is filtered off from the precipitated solid and the solid is washed neutral with water and dried. The crude product is boiled in 10 ml of ethanol, cooled, filtered and dried. 3.3I g of the title compound of m.p. 176°-176.5° C. (decomp.) are obtained.
D. 3-Methyl 5-(2-bromoethyl) (±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
10.65 g of a 80% suspension of sodium hydride in liquid paraffin are suspended in 300 ml of anhydrous tetrahydrofuran. A solution of 120 g of 3-methyl 5-(2-bromoethyl) (±)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 28.4 g of chloromethyl ethyl ether in 300 ml of anhydrous tetrahydrofuran is slowly added dropwise in the course of 4 h at -5° to -7° C., while stirring. After the mixture has been stirred for a further hour at 0° C., 600 ml of toluene and 210 ml of water are added in succession. The phases are separated, and the organic phase is washed with water, dried overnight and evaporated in vacuo. The residue is dissolved in 390 ml of warm ethanol and the stirred solution is then cooled. The product crystallises out during this procedure. It is cooled to 0° C., filtered off under suction, washed with ice-cold ethanol and dried. 98.5 g of the title compound of m.p. 72.5°-74° C. are obtained.
E. 3-Methyl 5-(2-bromoethyl) (±(-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
494 g of 2-bromoethyl 2-(3-nitrobenzylidene)-acetoacetate and 173.5 g of methyl 3-aminocrotonate are dissolved in 1750 ml of isopropanol at 75-80° C. while stirring and under a nitrogen atmosphere. The mixture is then cooled very slowly in a heating bath. The mixture is seeded with the title compound, after which it is stirred for 16 h at room temperature and then cooled, and the product is filtered off under suction, washed with ice-cold ether and dried. 481 g of the title compound of m.p. 139°-141° C. are obtained.
F. 2-Bromoethyl 2-(3-nitrobenzylidene)-acetoacetate
405 g of 2-bromoethyl acetoacetate are dissolved in 1500 ml of isopropanol. 293 g of 3-nitrobenzaldehyde, 4.6 g of acetic acid and 6.8 g of piperidine are added while stirring. The mixture is stirred at 40° C. until a clear solution has formed. The solution is allowed to cool slowly, seeded with a few crystals of the title compound and stirred at room temperature for 48 h and then cooled, and the product is filtered off under suction, washed with cold isopropanol and dried in vacuo at 50° C. 495 g of the title compound of m.p. 94.5°-95.5° C. are obtained.
G. 2-Bromoethyl acetoacetate
250 g of 2-bromoethanol are dissolved in 1.3 l of dichloromethane, and 1.2 g of 4-dimethylaminopyridine are added. 400 ml of a 50% strength diketene solution in acetone are added dropwise with vigorous stirring, so that the solvent boils moderately. After the dropwise addition, stirring is continued for a further 1 h at the boiling point and the mixture is then left to stand overnight. After the solvent has been evaporated off in a rotary evaportor in vacuo, the residue is distilled. 402 g of the title compound of b.p. 80°-83° C./0.04 mbar are obtained.
H. (+)-4-(2,3-dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylic acid
9.5 g of (±)-4-(2,3-dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylic acid and 6.75 g of cinchonidine are dissolved in 50 ml of methanol at the boil; the hot solution is filtered and then cooled. After seeding, the mixture is allowed to stand for several days at 0°-4° C., after which the product is filtered off under suction, washed with cold methanol and again recrystallised from methanol. 4.85 g of the cinchonidine salt of the title compound of m.p. 176°-178° C. are obtained. The salt is dissolved in 60 ml of chloroform. After the addition of 30 ml of water, the aqueous phase is adjusted to a pH of 2 by the addition of 2 N hydrochloric acid solution with vigorous stirring. After phase separation, the organic phase is washed 4 times with 0.01 N hydrochloric acid and once with water, dried over sodium sulphate and then evaporated in vacuo. The remaining crystalline residue is dried under high vacuum. 3.1 g of the title compound of m.p. 129°-131° C. and [α]22 D =+63.2° (c=1, chloroform) are obtained.
I. (±)-4-(2,3-Dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylic acid
Analogously to Example C, 9.5 g of the title compound of m.p. 156°-157° C. (from ethanol) are obtained from 14.25 g of 3-(2-bromoethyl) 5-methyl (±)-4-(2,3-dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethylpyridine-3,5dicarboxylate, 2.8 g of powdered sodium cyanide and a spatula tip of tetrabutylammonium cyanide in 60 ml of dimethylformamide after the addition of ml of 2 N sodium hydroxide solution and identical working up.
J. 3-(2-bromoethyl) 5-methyl (±)-4-(2,3-dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
Analogously to Example D, 14.3 g of the title compound of m.p. 104°-106° C. (from methanol) are obtained from 19.1 g of 3-(2-bromoethyl) 5-methyl (±)-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, 1.64 g of sodium hydride (80% in liquid paraffin), 4.75 g of chloromethyl ethyl ether and twice 50 ml of anhydrous tetrahydrofuran.
K. 3-(2-Bromoethyl) 5-methyl (±)-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
50 g of 2,3-dichlorobenzaldehyde and 60 g of 2-bromoethyl acetoacetate are dissolved in 400 ml of dichloromethane. 0.83 ml of glacial acetic acid, 1,4 ml of piperidine and 30 g of anhydrous sodium sulphate are added to the solution. The mixture is stirred for 4 days at room temperature, a further 20 g of anhydrous sodium sulphate being added after 2 days. After filtration under suction, the solution is washed with water. 0.1 N hydrochloric acid, dilute sodium bicarbonate solution and again with water and dried over sodium sulphate. After the solvent has been distilled off in vacuo, the oil residue is dissolved in 600 ml of tetrahydrofuran, and 33 g of methyl 3-aminocrotonate are added to the solution. The mixture is heated at the boil for 24 hours with nitrogen and cooled, after which the solvent is distilled off in vacuo, the residue is dissolved in dichloromethane and the solution is washed with 0.01 N hydrochloric acid and water. After drying over sodium sulphate, it is evaporated again. 150 ml of 2-propanol are added to the partially crystalline residue, the mixture is cooled and the product is filtered off under suction. Recrystallisation from 2-propanol gives 79 g of the title compound of m.p. 180°-182° C.
L. (+)-5-Ethoxycarbonyl-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid
37.5 g of (±)-5-ethoxycarbonyl-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid and 27.3 g of cinchonidine are dissolved in 450 ml of ethanol at the boil and then cooled slowly while stirring. After the mixture has been stirred for five days, it is filtered under suction and the residue is washed with ethanol and recrystallised 4 times from ethanol. The salt thus obtained (18.3 g) is dried and then dissolved in 300 ml of chloroform. After the addition of 150 ml of water, the pH is adjusted to 2 with 2 N hydrochloric acid solution while stirring vigorously. After phase separation, the organic phase is extracted by shaking 4 times with 0.01 N hydrochloric acid solution until cinchonidine can no longer be detected by thin-layer chromatography. It is washed neutral, dried over sodium sulphate and then evaporated, and the crystalline residue is dried under high vacuum. 10.6 g of the title compound of m.p. 133° C. (decomp.) and [α]22.sub. D =+82.5° (c=1, chloroform) are obtained.
M. (±)-5-Ethoxycarbonyl-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid
53.9 g of3-ethyl 5-(2-bromoethyl) (±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate are dissolved in 190 ml of dimethylformamide, and 10.85 g of powdered sodium cyanide and a spatula tip of tetrabutylammonium cyanide are added. After the mixture has been stirred for 60 h at room temperature. 110 ml of 2 N sodium hydroxide solution are added dropwise. After it has been stirred for a further 3 h, the mixture is stirred into 2 l of water. The pH is adjusted to 3 by the dropwise addition of 2 N hydrochloric acid solution while cooling with ice. The precipitate which separates out during this procedure is filtered off under suction, washed neutral with water and dried. For purification, it is boiled with 90 ml of ethanol, cooled, filtered off under suction and washed with cold ethanol. Following drying, 37.5 g of the title compound of m.p. 181°-182° C. (decomp.) are obtained.
N. 3-Ethyl 5-(2-bromoethyl) (±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
Analogously to starting compound D, 53.9 g of the title compound of m.p. 102°-104° C. (ethanol) are obtained from 64.9 g of 3-ethyl 5-(2-bromoethyl) (±)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 5.2 g of sodium hydride (80% in liquid paraffin), 14.9 g of chloromethyl ethyl ether and twice 130 ml of tetrahydrofuran.
O. 3-Ethyl 5-(2-bromoethyl) (±)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
58.8 g of 2-bromoethyl 2-(3-nitrobenzylidene)-acetoacetate and 22.5 g of ethyl 3-aminocrotonate in 250 ml of tetrahydrofuran are heated at the boil for 3 h. The mixture is stirred for 8 h at room temperature, after which the solvent is distilled off in vacuo and the solid residue is dissolved in hot 2-propanol. The title compound crystallises out on cooling. It is filtered off under suction, washed with cold 2-propanol and dried. 65 g of product of m.p. 158°-159° C. are obtained.
P. 3-Methyl 5-(3-bromopropyl) (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
168.5 g of (+)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonine salt {[α]22 D =+101.5° (c=1, chloroform)} (prepared from (±)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid and cinchonine analogously to Example B) are dissolved in 1.5 l of dichloromethane, after which 1.2 l of 0.2 N hydrochloric acid solution are added while cooling and stirring vigorously. By adding 2 N hydrochloric acid solution, a stable pH of 2 is obtained in the aqueous phase. After phase separation, the organic phase is washed four times with hydrochloric acid solution of pH 2 and then with water, dried over sodium sulphate and then evaporated. The oily residue is dissolved in 1.1 l of acetone, and 375 g of finely milled potassium carbonate, 375 ml of 1,3-dibromopropane and 1.2 g of [18]crown-6 are added. The mixture is stirred vigorously for 24 h at room temperature, then filtered under suction and the filter cake is washed with acetone. The filtrate is evaporated in a rotary evaporator under a slight vacuum, after which the excess 1,3-dibromopropane is distilled off at 0.02 mbar (bath temperature up to 45° C.). 690 ml of concentrated formic acid are poured over the oily residue after cooling with ice, after which stirring is carried out at room temperature until a clear solution has formed (about 15 min). The formic acid is distilled off in vacuo. After 200 ml portions of toluene have been added twice and distilled off twice, the residue is dissolved in 900 ml of dichloromethane. The solution is stirred thoroughly with sodium bicarbonate solution, washed with water, dried over sodium sulphate and evaporated in vacuo. The product which spontaneously crystallises after the addition of diisopropyl ether is filtered off under suction, washed with diisopropyl ether and dried in vacuo. 102 g of the title compound of m.p. 112°-114° C. and [α]22 D =-13.8° (c=1, methanol) are obtained.
Q. 3-Methyl 5-(2-bromoethyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
Analogously to starting compound A. 8.8 g of (-)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonidine salt are liberated and then reacted in 60 ml of acetone with 36 g of 1,2-dibromoethane, 3.9 g of finely powdered potassium carbonate and 0.1 g of [18]crown-6. After elimination of the protective group in 50 ml of concentrated formic acid and crystallisation from diisopropyl ether, 4.75 g of the title compound of m.p. 142°-144° C. (decomp.) and [α]22 D =+31.5° (c=1, chloroform) are obtained.
INDUSTRIAL APPLICATION
The pure enantiomeric compounds of the formula I prepared by the process according to the invention, and their salts, have valuable properties which make them industrially useful. They are, for example, effective vasodilators having therapeutic properties against coronary diseases. The pharmacological activity of the compounds according to the invention, which is coupled with low toxicity, is evident, for example, in a slow, pronounced and long-lasting lowering of blood pressure. Moreover, the compounds according to the invention have an inhibitory effect on calcium influx and promote the flow of potassium out of cells, relax smooth muscle, dilate peripheral, coronary, cerebral and renal vessels and have salidiuretic, antithrombotic, antiarteriosclerotic and advantageous haemorheological properties.
In their excellent efficacy, which is coupled with low toxicity and the lack of significant side effects, the enantiomers according to the invention differ in a surprising and advantageous manner from their racemates. Particularly surprising is the fact that the enantiomers according to the invention, which, in the 4-position of the dihydropyridine, have the same configuration as (-)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonidine salt, which can be used as a precursor and rotates linearly polarised light of wavelength 589 nm through [α]22 D =-63.4° (c=1, chloroform), and has substantially more pronounced antihypertensive action than the enantiomers having the mirror-image configuration.
By providing the enantiomers which are particularly efficacious in the main action, on the one hand the stress due to their less efficacious isostereomers, some of which may even have the opposite action or more pronounced side effects, is substantially reduced. On the other hand, the enantiomers which are less efficacious in the abovementioned main (antihypertensive) action can be used for other therapeutic purposes, which were previously not accessible to this class of substances--owing to the main action predominating in the racemates.
The following may be mentioned as examples of advantageous properties of the compound of I: the extent of lowering of blood pressure, the good controllability of the lowering of blood pressure, the surprisingly small, and for repeated administration vanishing, increase in heart rate, the excellent bioavailability, the high therapeutic index, the lack of central side effects, the lack of kinetic interactions with other substances, the absence of development of tolerance, the well balanced physical properties and the high stability.
The excellent efficacy of the compounds according to the invention, of the formula I, and their salts permit their use in human medicine, examples of their indications being primary (essential) and secondary, arterial and pulmonal hypertensions of all severity levels, coronary heart diseases (coronary insufficiency, angina pectoras, myocardial infarction, etc.), peripheral and cerebral circulatory disorders (stroke, temporary cerebral blood-flow disturbances, migraine, giddiness, narrowing of renal arteries, etc.), hypertrophic cardiomyopathy, cardiac insufficiency, disorders due to increased water retention and sodium retention and disorders due to an increased influx of calcium, such as, for example, spasms of organs containing smooth muscle (respiratory tract, gastrointestinal tract, urogenital tract, etc.) and arrhythmia, arteriosclerosis and cell damage of various origins (for example hypoxia).
The invention therefore also relates to a method for the treatment of mammals, in particular humans, suffering from one of the above-mentioned disorders. The method is characterised in that the suffering individual is administered a therapeutically effect and pharmacologically acceptable amount of one or more compounds of the formula I.
The invention furthermore relates to compounds of the formula I for use in the treatment of the stated disorders.
The invention also relates to the use of the compounds of the formula I for the preparation of medicaments which are used for the treatment of the stated disorders.
The invention furthermore relates to medicaments which contain one or more compounds of the general formula I.
The medicaments are prepared by processes known per se and familiar to the skilled worker. The pharmacologically effective compounds (=active ingredients) according to the invention are used either as such or, preferably, in combination with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions, aerosols, sprays, ointments, creams, gels or solutions, the content of active ingredient advantageously being between 0.1 and 95%.
On the basis of his technical knowledge, the skilled worker knows which auxiliaries are suitable for the desired drug formulations. In addition to solvents, gel formers, suppository bases, tabletting auxiliaries and other excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavourings, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example cyclodextrins).
The active ingredients may be administered orally, rectally, by inhalation or parenterally (in particular perlingually, intravenously or percutaneously).
In general, it has proved advantageous in human medicine to administer the active ingredient or ingredients in a daily dose of about 0.01 to about 10, preferably 0.05 to 5, mg/kg body weight in the case of oral administration, if desired in the form of several, preferably 1 to 4, individual doses, in order to achieve the desired result. In the case of parenteral treatment, similar or (in particular in the case of intravenous administration of the active ingredient) as a rule lower doses may be used. In the case of increasing dosage, a low dose is administered at the beginning of the treatment, after which higher doses are slowly introduced. After the desired therapeutic success has been attained, the dose is returned to a lower level.
The particular required optimal dose and mode of administration of the active ingredients can easily be determined by any skilled worker on the basis of his technical knowledge.
If the compounds according to the invention and/or their salts are used for the treatment of the stated disorders, the pharmaceutical formulations may also contain one or more other pharmacologically active constituents of other groups of medicaments, such as other vasodilators, antihypertensive agents, alpha-1-receptor blockers, alpha-2-receptor stimulators, beta-1-receptor blockers, beta-2-receptor stimulators. ACE inhibitors, nitro compounds, cardio tonic agents, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergic agents, methylxanthines, antiarrhythmics, antihistamines, dopamine stimulators, serotonine receptor blockers, etc., such as nifedipine dihydralazine prazosine, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, rauwolfia total alkaloids, acetylsalicylic acid, bezafibrate, warfarin, atropine, theophylline, lidocaine, astemizole, bromocryptine, ketanserine, etc.
PHARMACOLOGY
The antihypertensive activity of the compounds according to the invention can be demonstrated in the model of the spontaneously hypertensive rat.
For determination of the antihypertensive action, the compounds mentioned below are administered in the stated doses, on four successive days, to 6 male rats (strain SHR/N/Ibm/Bm, 250-350 g) with genetic high blood pressure (systolic high blood pressure >180 mmHg), once daily by means of a stomach tube. The blood pressure is measured in each case 6 and, if necessary. 2 or 24 hours after administration of the substance.
The blood pressure measurement is carried out in a heated chamber at 36° C. in order to achieve better flow through the caudal artery. For this purpose, the animals are placed in perforated metal cages and measurements are carried out 20-40 min after the beginning of heating. To measure the systolic arterial pressure, an annula collar with an inflatable rubber membrane for suppressing blood flow and an annula piezocrystalline pick-up for detecting the pulse waves are pushed onto the tail. After the blood flow in the caudal artery has been suppressed, the collar pressure is reduced continuously. The return of the pulse waves when the pressure is let down is detected automatically as systolic blood pressure and is printed out (Buhler, R. et. al.: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 1982, pages 410-413). The pulse signals and pressure curve are plotted graphically for evaluation.
To condition them to the measuring process, the animals are trained for 14 days before testing of the substance. In the second week of training, preliminary blood pressure values are measured. Groups of animals which receive the substance are tested against a control group. In the Table below, the compounds investigated are denoted by serial numbers which correspond to the particular example numbers.
Table I shows the percentage lowering of blood pressure (BP) after oral administration in the rat for typical compounds according to the invention.
              TABLE I                                                     
______________________________________                                    
% changes (BP) in genetically hypertensive rats after a single            
daily oral administration on four successive days (N = 6/dose).           
             BP ( change vs. control),                                    
Ex-          mean value for measuring times:                              
am-  Dose    hours after administration (days)                            
ple  μmol/                                                             
             2h          6h        24h                                    
No.  kg      (1st + 4th day)                                              
                         (1st - 4th day)                                  
                                   (1st + 3rd day)                        
______________________________________                                    
1    25      -36         -26       0                                      
3     3      -13         -13       -2                                     
______________________________________

Claims (22)

We claim:
1. A pure dihydropyridine enantiomer of formula I ##STR23## wherein Cy represents a cyclic radical of the formula ##STR24## in which Y denotes oxygen (O), sulphur (S), vinylene (--CH═CH--), azomethine (--CH═N--) or a group of the formula ##STR25## R1 and R2 are identical or different and denote hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,
R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl,
R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl or 2-5C-acyl or together denote methylenedioxy, or denote amino or mono- or di-1-4C-alkylamino,
E denotes straight-chain or branched 2-5C-alkylene which may be substituted by 1-4C-alkoxy or aryl,
A denotes --CH2 --C(R6)R7--CH2 -- or --CH2 -NR8--CH2 --,
R6 denotes hydrogen (H) or aryl and
R7 denotes aryl or arylcarbonyl
R8 denotes aryl, aryl-1-4-C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, aryl representing a ring of the formula ##STR26## wherein R9 and R10 are identical or different and have the meaning of hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxyl or trifluoromethyl, and heteroaryl represents a 5-membered or 6-membered heterocylic radical having one heteroatom or two identical or different heteroatoms from the group consisting of oxygen (O), sulphur (S) or nitrogen (N), which is unsaturated or partially or completely saturated and which may carry one or two substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl or cyano, and the salts of these compounds, except for the (S)-enantiomer of the compound in which Cy has the meaning of 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene, A represents CH2 --C(R6)R7--CH2 and R6 and R7 denote phenyl.
2. A pure enantiomeric compound of formula I according to claim 1, wherein
Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl,
R1 and R2 are identical or different and denote 1-4C-alkyl,
R3 denotes 1-4C-alkyl,
E denotes ethylene or propylene,
A denotes --CH2 --C(R6)R7--CH2 -- or --CH2 --NR8--CH2 --,
R6 denotes hydrogen (H) or phenyl,
R7 denotes phenyl and
R8 denotes aryl or benzhydryl, aryl representing a ring of the formula ##STR27## wherein R9 and R10 are identical or different and denote hydrogen (H), 1-4C-alkoxy or halogen,
and the salts of these compounds, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene, A represents CH2 --C(R6)R7--CH2 and R6 and R7 denote phenyl.
3. A pure enantiomeric compound of claim 1 of formula Ia ##STR28## wherein Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene,
R6 denotes hydrogen and
R7 denotes phenyl, benzoyl, 4-chlorobenzoyl or 4-fluorobenzoyl, and their salts.
4. A pure enantiomeric compound of claim 1 of formula Ib ##STR29## wherein Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene and
R8 denotes phenyl 2-methoxyphenyl, 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl. 2,6-dimethylphenyl, 2-pyridyl or benzhydryl, and their salts.
5. A pure enantomeric compound of claim 1 of formula Ic ##STR30## wherein Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
E denotes ethylene or propylene,
R6 denotes phenyl or 4-methoxyphenyl and
R7 denotes phenyl or 4-methoxyphenyl,
and their salts, except for the (S)-enantiomer of the compound in which Cy denotes 3-nitrophenyl, R1, R2 and R3 denote methyl, E denotes propylene and R6 and R7 denote phenyl.
6. A process for the preparation of pure enantiomeric compounds of the formula I ##STR31## wherein Cy represents a cyclic radical of the formula ##STR32## in which Y denotes oxygen (O), sulphur (S), vinylene (--CH═CH--), azomethine (--CH═N--) or a group of the formula ##STR33## R1 and R2 are identical or different and denote hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,
R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl,
R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl or 2-5C-acyl or together denote methylenedioxy, or denote amino or mono- or di-1-4C-alkylamino,
E denotes straight-chain or branched 2-5C-alkylene which may be substituted by 1-4C-alkoxy or aryl,
A denotes --CH2 --C(R6)R7--CH2 -- or --CH2 --NR8--CH2 --,
R6 denotes hydrogen (H) or aryl and
R7 denotes aryl or arylcarbonyl,
R8 denotes aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, aryl representing a ring of the formula ##STR34## wherein R9 and R10 are identical or different and have the meaning of hydrogen (H), 1-4C-alkyl, 1-4C -alkoxy, halogen, hydroxyl or trifluoromethyl, and heteroaryl represents a 5-membered or 6-membered heterocylic radical having one heteroatom or two identical or different heteroatoms from the group consisting of oxygen (O), sulphur (S) or nitrogen (N). which is unsaturated or partially or completely saturated and which may carry one or two substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl or cyano, and their salts, characterised in that pure enantiomeric N-protected dihydropyridinecarboxylic acids of the formula II ##STR35## wherein R1, R2, R3 and Cy have the above-mentioned meanings and SG represents a protective group, are reacted with an omega-dihaloalkane Hal-E-Hal, wherein Hal denotes halogen and E has the above-mentioned meaning, and, after elimination of the protective group SG, the resulting haloalkyl ether III ##STR36## is reacted with an amine of the formula IV or a salt thereof ##STR37## wherein A has the above-mentioned meaning, and, if desired, salts of the compound I which are obtained are then converted into the free bases or the compounds I are converted into their salts.
7. Process according to claim 6 for the preparation of 3-methyl 5-[3-(4,4-diphenylpiperid-1-yl)-propyl] (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate of the formula I* and its salts ##STR38## characterised in that an N-protected dihydropyridinecarboxylic acid of the formula II* ##STR39## is reacted with 1,3-dibromopropane and, after elimination of the protective group SG, the resulting bromopropyl ester III* ##STR40## is reacted with diphenylpiperidine or a salt thereof and, if desired, a resulting salt of the compound I* is then converted into the free base or the compound I* is converted into a salt.
8. Process according to claim 6, characterized in that the protective group SG is an alkoxymethyl group or benzyloxymethyl group.
9. A medicament composition useful for treating and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention and which comprises an effective amount of an enantiomer of claim 1 or of a pharmacologically-acceptable salt thereof in combination with suitable auxiliary or excipient.
10. A medicament composition useful for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention and which comprises an effective amount of a compound of claim 2 or of a pharmacologically-acceptable salt thereof in combination with suitable auxiliary or excipient.
11. A medicament composition useful for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention and which comprises an effective amount of a compound of claim 3 or of a pharmacologically-acceptable salt thereof in combination with suitable auxiliary or excipient.
12. A medicament composition useful for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention and which comprises an effective amount of a compound of claim 4 or of a pharmacologically-acceptable salt thereof in combination with suitable auxiliary or excipient.
13. A medicament composition useful for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention and which comprises an effective amount of a compound of claim 5 or of a pharmacologically-acceptable salt thereof in combination with suitable auxiliary or excipient.
14. A method for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention which comprises administering an effective amount of an enantiomer of claim 1 or of a pharmacologically-acceptable salt thereof to a mammal subject to or afflicted with one of the preceding conditions.
15. A method for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention which comprises administering an effective amount of a compound of claim 2 or of a pharmacologically-acceptable salt thereof to a mammal subject to or afflicted with one of the preceding conditions.
16. A method for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention which comprises administering an effective amount of a compound of claim 3 or of a pharmacologically-acceptable salt thereof to a mammal subject to or afflicted with one of the preceding conditions.
17. A method for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention which comprises administering an effective amount of a compound of claim 4 or of a pharmacologically-acceptable salt thereof to a mammal subject to or afflicted with one of the preceding conditions.
18. A method for treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders, disorders due to increased water retention and disorders due to increased sodium retention which comprises administering an effective amount of a compound of claim 5 or of a pharmacologically-acceptable salt thereof to a mammal subject to or afflicted with one of the preceding conditions.
19. A pure enantiomer of claim 1 which, in the 4-position of the dihydropyridine, has the same configuration as the (+)-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid cinchonine salt which can be used as a precursor and which rotates linearly polarized light of wavelength 589 nm through [α]22 D =+101.5° (c=1, methanol); or a salt thereof.
20. A pure enantiomer of claim 19 which is (-)-3-methyl-5-[3-(4,4-diphenyl-1-piperidinyl)-propyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate or a pharmacologically-acceptable salt thereof.
21. An antiarteriosclerotic composition comprising an effective amount of a compound of claim 19 or of a pharmacologically-acceptable salt thereof and a pharmacologically-acceptable carrier.
22. A method for treatment and/or prophylaxis of arteriosclerosis which comprises administering an effective amount of an enantiomer of claim 19 or of a pharmacologically-acceptable salt thereof to a mammal subject to or afflicted with arteriosclerosis.
US07/401,453 1987-03-27 1988-03-24 1,4-dihydropyridine enantiomers Expired - Fee Related US4994461A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH119087 1987-03-27
CH01184/87 1987-03-27
CH118487 1987-03-27
CH01190/87 1987-03-27

Publications (1)

Publication Number Publication Date
US4994461A true US4994461A (en) 1991-02-19

Family

ID=25686924

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/401,453 Expired - Fee Related US4994461A (en) 1987-03-27 1988-03-24 1,4-dihydropyridine enantiomers

Country Status (8)

Country Link
US (1) US4994461A (en)
EP (2) EP0296316B1 (en)
JP (1) JP2625190B2 (en)
AU (1) AU1626488A (en)
CZ (1) CZ281597B6 (en)
DE (1) DE3883627D1 (en)
ES (1) ES2059416T3 (en)
WO (1) WO1988007525A1 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5100892A (en) * 1990-11-13 1992-03-31 Glaxo Inc. Dihydropyridine vasodilator agents
US5326772A (en) * 1984-09-28 1994-07-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Diaryl compounds for their use
US5403847A (en) * 1992-11-13 1995-04-04 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperlasia
US5470860A (en) * 1991-12-13 1995-11-28 Byk Gulden Lomberg Chemische Fabrik Gmbh 1,4-dihydropyridines for use in the treatment of dermatoses
US5578611A (en) * 1992-11-13 1996-11-26 Synaptic Pharmaceutical Corporation Use of α-1C specific compounds to treat benign prostatic hyperplasia
US5767131A (en) * 1993-04-05 1998-06-16 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
US6015819A (en) * 1992-11-13 2000-01-18 Synaptic Pharmaceutical Corporation Use of alpha-1C specific compounds to treat benign prostatic hyperplasia
US6211198B1 (en) 1993-04-05 2001-04-03 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
US20070238716A1 (en) * 2006-03-14 2007-10-11 Murthy Ayanampudi S R Statin stabilizing dosage formulations
US20080153896A1 (en) * 2006-07-14 2008-06-26 Gyan Chand Yadav Polymorphic Forms of an HMG-CoA Reductase Inhibitor and Uses Thereof
US20080248035A1 (en) * 2005-11-08 2008-10-09 Ranbaxy Laboratories Pharmaceutical Combination
US20100056602A1 (en) * 2003-05-30 2010-03-04 Ranbaxy Laboratories Limited Substituted Pyrrole Derivatives And Their Use As HMG-CO Inhibitors
EP2251337A1 (en) * 2008-01-21 2010-11-17 Cosunter Pharmaceutical Company Dihydropyridine calcium antagonist compounds, preparation methods and medical uses thereof
US9018376B2 (en) 2009-08-27 2015-04-28 Cipla Limited Polymorphic forms of manidipine
CN105924382A (en) * 2016-06-20 2016-09-07 扬子江药业集团北京海燕药业有限公司 S-Manidipine hydrochloride crystal form I and preparation method thereof
CN106083698A (en) * 2016-06-20 2016-11-09 扬子江药业集团北京海燕药业有限公司 S Manidipine hydrochloride polymorph and preparation method thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1230752B (en) * 1989-02-17 1991-10-29 Boehringer Biochemia Srl PROCESS FOR THE PREPARATION OF 1,4 POLY-SUBSTITUTED DIHYDROPYRIDINS IN AN ANTIOMERICALLY PURE FORM.
JPH03141257A (en) * 1989-10-26 1991-06-17 Green Cross Corp:The Dihydropyridine derivative
DE4041814A1 (en) * 1990-12-24 1992-07-02 Byk Gulden Lomberg Chem Fab METHOD FOR PRODUCING DIHYDROPHYRIDINE CARBONIC ACIDS

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4031104A (en) * 1972-04-18 1977-06-21 Bayer Aktiengesellschaft 1,4-Dihydropyridine carboxylic acid esters
US4145432A (en) * 1975-07-02 1979-03-20 Fujisawa Pharmaceutical Co., Ltd. 6-acyloryalkyl-1,4-dihydropyridine derivatives and a method of effecting vasodilation therewith
US4380547A (en) * 1980-06-12 1983-04-19 Bayer Aktiengesellschaft Dihydropyridine compounds which are substituted in the 4-position by imidazolyl or thiazolyl and their medicinal use
US4491582A (en) * 1983-03-03 1985-01-01 Usv Pharmaceutical Corporation N-(substituted piperazino)-1,4-dihydropyridine-3,5-carboxylic acid
US4497808A (en) * 1981-12-30 1985-02-05 Ciba-Geigy Corporation N-Oxide compounds useful in the treatment of cardiovascular ailments
US4505920A (en) * 1983-03-03 1985-03-19 Usv Pharmaceutical Corporation Certain N-substituted-4-aryl-3,5-pyridine dicarboxylates and their antihypertensive use
US4510310A (en) * 1979-09-01 1985-04-09 Bayer Aktiengesellschaft 1,4-Dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-3,5-dicarboxylic acid,methyl or ethyl,trifluoroethyl ester
US4558058A (en) * 1982-12-20 1985-12-10 Cassella Aktiengesellschaft Substituted 1,4-dihydropyridines and their use as medicaments
US4603135A (en) * 1983-10-17 1986-07-29 Takeda Chemical Industries, Ltd. Substituted piperazinyl alkyl esters of 2-amino-4-aryl-1,4-dihydro-6-alkyl-3,5-pyridinedicarboxylates
US4707486A (en) * 1984-09-28 1987-11-17 Byk Gulden Lomberg Chemische Fabrik Gmbh Diaryl piperidine containing esters of 1,4-dihydropyridines and coronary therapeutic use

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985000169A1 (en) * 1983-06-21 1985-01-17 Sandoz Ag 1,4-dihydropyridine derivatives, production thereof and pharmaceutical preparations containing them
DE3431152A1 (en) * 1984-08-24 1986-03-06 Cassella Ag, 6000 Frankfurt METHOD FOR PRODUCING OPTICALLY ACTIVE, SUBSTITUTED 1,4-DIHYDROPYRIDINE AND THEIR USE AS A MEDICINAL PRODUCT
EP0174654A3 (en) * 1984-09-14 1987-07-22 Ciba-Geigy Ag Carbonyl derivatives
WO1986003748A1 (en) * 1984-12-21 1986-07-03 Byk Gulden Lomberg Chemische Fabrik Gesellschaft M New piperazine derivatives
DE3627742A1 (en) * 1985-08-20 1987-02-26 Byk Gulden Lomberg Chem Fab Substituted 1,4-dihydropyridine-3-carboxylic acid derivatives
DK114587A (en) * 1986-03-12 1987-09-13 Byk Gulden Lomberg Chem Fab MONOCYCLIC ESTER DERIVATIVES
DK142287A (en) * 1986-03-27 1987-09-28 Byk Gulden Lomberg Chem Fab OPTIC ACTIVE 1,4-DIHYDROPYRIDINE DERIVATIVES
NZ220022A (en) * 1986-04-22 1990-04-26 Byk Gulden Lomberg Chem Fab 1,4-dihydropyridine derivatives and pharmaceutical compositions

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4031104A (en) * 1972-04-18 1977-06-21 Bayer Aktiengesellschaft 1,4-Dihydropyridine carboxylic acid esters
US4145432A (en) * 1975-07-02 1979-03-20 Fujisawa Pharmaceutical Co., Ltd. 6-acyloryalkyl-1,4-dihydropyridine derivatives and a method of effecting vasodilation therewith
US4510310A (en) * 1979-09-01 1985-04-09 Bayer Aktiengesellschaft 1,4-Dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-3,5-dicarboxylic acid,methyl or ethyl,trifluoroethyl ester
US4380547A (en) * 1980-06-12 1983-04-19 Bayer Aktiengesellschaft Dihydropyridine compounds which are substituted in the 4-position by imidazolyl or thiazolyl and their medicinal use
US4497808A (en) * 1981-12-30 1985-02-05 Ciba-Geigy Corporation N-Oxide compounds useful in the treatment of cardiovascular ailments
US4558058A (en) * 1982-12-20 1985-12-10 Cassella Aktiengesellschaft Substituted 1,4-dihydropyridines and their use as medicaments
US4491582A (en) * 1983-03-03 1985-01-01 Usv Pharmaceutical Corporation N-(substituted piperazino)-1,4-dihydropyridine-3,5-carboxylic acid
US4505920A (en) * 1983-03-03 1985-03-19 Usv Pharmaceutical Corporation Certain N-substituted-4-aryl-3,5-pyridine dicarboxylates and their antihypertensive use
US4603135A (en) * 1983-10-17 1986-07-29 Takeda Chemical Industries, Ltd. Substituted piperazinyl alkyl esters of 2-amino-4-aryl-1,4-dihydro-6-alkyl-3,5-pyridinedicarboxylates
US4707486A (en) * 1984-09-28 1987-11-17 Byk Gulden Lomberg Chemische Fabrik Gmbh Diaryl piperidine containing esters of 1,4-dihydropyridines and coronary therapeutic use

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Shibanuma et al. Chem. Pharm. Bull. 28(9) 2809 2812 (1980). *
Shibanuma et al. Chem. Pharm. Bull. 28(9) 2809-2812 (1980).
Tamazawa, J. Med. Chem., 29, 2504 to 2511, 1986. *
Wehinger et al, Chem Abst. 105 133753f (1986). *
Wehinger et al, Chem Abst. 105-133753f (1986).

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5326772A (en) * 1984-09-28 1994-07-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Diaryl compounds for their use
US5100892A (en) * 1990-11-13 1992-03-31 Glaxo Inc. Dihydropyridine vasodilator agents
US5470860A (en) * 1991-12-13 1995-11-28 Byk Gulden Lomberg Chemische Fabrik Gmbh 1,4-dihydropyridines for use in the treatment of dermatoses
US5780485A (en) * 1992-11-13 1998-07-14 Synaptic Pharmaceutical Corporation Use of α1c specific compounds to treat benign prostatic hyperplasia
US5578611A (en) * 1992-11-13 1996-11-26 Synaptic Pharmaceutical Corporation Use of α-1C specific compounds to treat benign prostatic hyperplasia
US5403847A (en) * 1992-11-13 1995-04-04 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperlasia
US6015819A (en) * 1992-11-13 2000-01-18 Synaptic Pharmaceutical Corporation Use of alpha-1C specific compounds to treat benign prostatic hyperplasia
US6602888B2 (en) 1992-11-13 2003-08-05 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperplasia
US5767131A (en) * 1993-04-05 1998-06-16 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
US6211198B1 (en) 1993-04-05 2001-04-03 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
US6310076B1 (en) 1993-04-05 2001-10-30 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
US6608086B2 (en) 1993-04-05 2003-08-19 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
US5990128A (en) * 1994-04-13 1999-11-23 Synaptic Pharmaceutical Corporation α1C specific compounds to treat benign prostatic hyperplasia
US20110190296A1 (en) * 2003-05-30 2011-08-04 Ranbaxy Laboratories Limited Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors
US20100056602A1 (en) * 2003-05-30 2010-03-04 Ranbaxy Laboratories Limited Substituted Pyrrole Derivatives And Their Use As HMG-CO Inhibitors
US20110190369A1 (en) * 2003-05-30 2011-08-04 Ranbaxy Laboratories Limited Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors
US7923467B2 (en) 2003-05-30 2011-04-12 Ranbaxy Laboratories, Inc. Substituted pyrrole derivatives and their use as HMG-CO inhibitors
US7671216B2 (en) 2005-11-08 2010-03-02 Ranbaxy Laboratories Limited Process for preparation of (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt
US20080248035A1 (en) * 2005-11-08 2008-10-09 Ranbaxy Laboratories Pharmaceutical Combination
US20090118520A1 (en) * 2005-11-08 2009-05-07 Ranbaxy Laboratories Limited Process for preparation of (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt
US8026377B2 (en) 2005-11-08 2011-09-27 Ranbaxy Laboratories, Limited Process for (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt
US20080287690A1 (en) * 2005-11-08 2008-11-20 Ranbaxy Laboratories Limited Process For (3R, 5R)-7-[2-(4-Fluorophenyl)-5-Isopropyl-3-Phenyl-4- [(4-Hydroxy Methyl Phenyl Amino) Carbonyl]-Pyrrol-1-Yl]-3,5-Dihydroxy-Heptanoic Acid Hemi Calcium Salt
US7956198B2 (en) 2005-11-08 2011-06-07 Ranbaxy Laboratories, Limited Pharmaceutical compositions
US20070238716A1 (en) * 2006-03-14 2007-10-11 Murthy Ayanampudi S R Statin stabilizing dosage formulations
US20080153896A1 (en) * 2006-07-14 2008-06-26 Gyan Chand Yadav Polymorphic Forms of an HMG-CoA Reductase Inhibitor and Uses Thereof
EP2251337A4 (en) * 2008-01-21 2011-03-30 Cosunter Pharmaceutical Company Dihydropyridine calcium antagonist compounds, preparation methods and medical uses thereof
EP2251337A1 (en) * 2008-01-21 2010-11-17 Cosunter Pharmaceutical Company Dihydropyridine calcium antagonist compounds, preparation methods and medical uses thereof
US9018376B2 (en) 2009-08-27 2015-04-28 Cipla Limited Polymorphic forms of manidipine
CN105924382A (en) * 2016-06-20 2016-09-07 扬子江药业集团北京海燕药业有限公司 S-Manidipine hydrochloride crystal form I and preparation method thereof
CN106083698A (en) * 2016-06-20 2016-11-09 扬子江药业集团北京海燕药业有限公司 S Manidipine hydrochloride polymorph and preparation method thereof
CN105924382B (en) * 2016-06-20 2018-08-03 扬子江药业集团北京海燕药业有限公司 S- Manidipine hydrochloride I crystals and preparation method thereof
CN106083698B (en) * 2016-06-20 2018-08-03 扬子江药业集团北京海燕药业有限公司 S- Manidipine hydrochloride polymorphs and preparation method thereof

Also Published As

Publication number Publication date
WO1988007525A1 (en) 1988-10-06
EP0296316B1 (en) 1993-09-01
CZ281597B6 (en) 1996-11-13
CZ396591A3 (en) 1996-06-12
JPH02502823A (en) 1990-09-06
JP2625190B2 (en) 1997-07-02
DE3883627D1 (en) 1993-10-07
ES2059416T3 (en) 1994-11-16
EP0343193A1 (en) 1989-11-29
AU1626488A (en) 1988-11-02
EP0296316A1 (en) 1988-12-28

Similar Documents

Publication Publication Date Title
US4994461A (en) 1,4-dihydropyridine enantiomers
US4822798A (en) Circulation-active 4-phenyl-6-substituted dihydropyrimidines
US4707486A (en) Diaryl piperidine containing esters of 1,4-dihydropyridines and coronary therapeutic use
JPH0542431B2 (en)
EP0060674A1 (en) Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them
JPS6339588B2 (en)
US4772612A (en) Circulation-active 1,4-dihydropyridines
EP0164247B1 (en) Dihydropyridines
EP0197488A2 (en) 1,4-Dihydropyiridine derivative, a process for preparing the same, a pharmaceutical composition as well as the use thereof
JPS61257983A (en) 1,4-dihydropyridine and medicinal composition
JPH0316955B2 (en)
US5064839A (en) 1,4-dihydropyridines with a 2-amino group or with an ether group in a side chain
US4876255A (en) Substituted 1,4-dihydropyridines for control of circulation and thromboses
US4639522A (en) 1-benzyl-3,5-dimethyl-4-piperdyl ester of a Hantzsch dihydropyridine
US4547502A (en) Dihydropyridines and their use in treating cardiac conditions and hypertension
US4876254A (en) Circulation-active substituted 5-nitro-1,4-dihydropyridines
JPH02169572A (en) Dihydropyridineamide and its physiologically
JPS62226960A (en) Monocyclic ester, its production and drug for treating and preventing hypertension, coronary heart disease, terminal and brain circulatory disorder and/or disease caused by enhanced water or sodium storage
EP0184841A2 (en) 1,4-Dihydropyridine derivatives, processes for their preparation and pharmaceutical compositions containing same
WO1988007531A1 (en) New optically active compounds
HU196791B (en) Process for producing new, optically active dihydropyridines and pharmaceutical compositions containing them
CA1291137C (en) 1,4-dihydropyridines with diphenylpiperidylester group
JPH01168683A (en) Novel substituted nitrodihydropyridine and its production and use
NZ226717A (en) Substituted pyrrolidine-alkyl 1,4-dihydropyridine carboxylate derivatives and medicaments
WO1988002750A1 (en) 1,4-dihydropyridine

Legal Events

Date Code Title Description
AS Assignment

Owner name: BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ULRICH, WOLF-RUDIGER;REEL/FRAME:005221/0609

Effective date: 19890908

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 19990219

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362